Indole derivatives as 5-HT receptor antagonist

ABSTRACT

A compound of formula (I) or a salt thereof:                    
     wherein: 
     P 1  is pyridiyl; 
     P 2  is phenyl; 
     A is a bond or a chain of 1 to 5 atoms optionally substituted by C 1-6  alkyl; 
     R 1  and R 2  groups are each independently hydrogen, C 1-6 alkyl optionally substituted by NR 12 R 13 , C 2-6 alkenyl, C 2-6 alkynyl, cyano, halogen, CF 3 , NR 12 R 13 , CHO, OCF 3 , COR 14 , CH 2 OR 14  or OR 14  where R 12 , R 13  and R 14  are independently hydrogen or C 1-6 alkyl; 
     n and m are independently 0, 1 or 2; 
     R 3  is hydrogen or C 1-6  alkyl; 
     R 4  is a group of formula (i):                    
     in which: 
     R 6  and R 7  are independently hydrogen, C 1-6  alkyl optionally substituted by one or more fluorine atoms, C 1-6 alkylthio, C 1-6 alkoxy or halogen.

CROSS REFERENCE

This application is a 371 of PCT/EP96/00368 filed Jan. 26, 1996, whichis a division of Ser. No. 08/875,506 filed Oct. 16, 1997 U.S. Pat. No.5,990,133.

This invention relates to compounds having pharmacological activity,processes for their preparation, to compositions containing them and totheir use in the treatment of CNS disorders.

WO 94/04533 (Smith Kline Beecham plc) describes indole and indolinederivatives which are described as possessing 5HT_(2C) receptorantagonist activity. A structurally distinct class of compounds has nowbeen discovered, which have been found to have 5HT_(2C) receptorantagonist activity. Certain compounds of the invention also exhibit5HT_(2B) antagonist activity. 5HT_(2C/2B) receptor antagonists arebelieved to be of potential use in the treatment of CNS disorders suchas anxiety, depression, epilepsy, obsessive compulsive disorders,migraine, Alzheimers disease, sleep disorders, feeding disorders such asanorexia and bulimia, panic attacks, withdrawal from drug abuse such ascocaine, ethanol nicotine and benzodiazepines, schizophrenia, and alsodisorders associated with spinal trauma and/or head injury such ashydrocephalus. Compounds of the invention are also expected to be of usein the treatment of certain GI disorders such as IBS as well asmicrovascular diseases such as macular oedema and retinopathy.

The present invention therefore provides, in a first aspect, a compoundof formula (I) or a salt thereof:

wherein:

P¹ and P² are independently phenyl, aromatic or partially saturatedmonocyclic or bicyclic heterocyclic rings containing up to threeheteroatoms selected from nitrogen, oxygen or sulphur;

A is a bond, a chain of 1 to 5 atoms optionally substituted by C₁₋₆alkyl or A is an optionally substituted phenyl or an optionallysubstituted 5- to 7-membered heterocyclic ring containing up to threeheteroatoms selected from nitrogen, oxygen or sulphur;

R¹ and R² groups are each independently hydrogen, C₁₋₆ alkyl optionallysubstituted by NR¹²R¹³, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkylthio,cyano, nitro, halogen, CF₃, C₂F₅, NR¹²R¹³, CONR¹²R¹³, NR¹²COR¹³,S(O)_(p)NR¹²R¹³, CHO, OCF₃, SCF₃, COR¹⁴, CH₂OR¹⁴, CO₂R¹⁴ or OR¹⁴ where pis 1 or 2 and R¹², R¹³ and R¹⁴ are independently hydrogen, C₁₋₆ alkyl,optionally substituted aryl or optionally substituted arylC₁₋₆alkyl;

n and m are independently 0, 1 or 2;

R³ is hydrogen or C₁₋₆ alkyl;

R⁴ is a group of formula (i):

in which:

X and Y are both nitrogen, one is nitrogen and the other is carbon or aCR⁵ group or one is a CR⁵ group and the other is carbon or a CR⁵ group;

R⁵, R⁶, R⁷ and R⁸ groups are independently hydrogen, C₁₋₆ alkyloptionally substituted by one or more fluorine atoms, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, C₃₋₆ cycloaklylC₁₋₆alkoxy, C₂₋₆ alkynyl, C₃₋₆ cycloaklyloxy,C₃₋₆ cycloaklyl-C₁₋₆ alkyl, C₁₋₆ alkylthio, C₃₋₆ cycloaklythio, C₃₋₆cycloaklyl-C₁₋₆ alkythio, C₁₋₆alkoxy, hydroxy, halogen, nitro, OCF₃,SCF₃, SO₂CF₃, SO₂F, formyl, C₂₋₆ alkanoyl, cyano, optionally substitutedphenyl or thienyl, NR¹²R¹³, CONR¹²R¹³ or CO₂R¹⁴ where where R¹², R¹³ andR¹⁴ are as defined for R¹; R⁶ and R⁷ from part of an optionallysubstituted 5- or 6-membered carbocyclic or heterocyclic ring;

R⁹ and R¹⁰ are independently hydrogen or C₁₋₆ alkyl; or

R⁴ is a group of formula (ii):

in which X and Y are both nitrogen, none is nitrogen and the other is aCR⁵ group or X and Y are both CR⁵ groups, and R⁵, R⁶, R⁷ and R⁸ are asdefined in formula (I); and

R¹¹ is hydrogen or C₁₋₆ alkyl, or

R⁴ is a group of formula (iii):

in which R⁶, R⁷, X and Y are as defined in formula (i) and Z is O, S,CH₂ or NR¹⁵ where R¹⁵ is hydrogen or C₁₋₆ alkyl.

C₁₋₆ Alkyl groups, whether alone or as part of another group, may bestraight chain or branched.

Suitably A is a bond or a chain of 1 to 5 atoms optionally substitutedby C₁₋₆ alkyl. Examples of such chains include (CH₂)_(p)X or X(CH₂)_(p)where p is 1 to 4 and X is CO, O, S(O)_(x) where x is 0 to 2 or A is NR,CONR, NRCO, NRCONR, CO, CH(OH), C₁₋₆alkyl, CH═CH, CH═CF, CF═CF, O,S(O)_(x) where x is 1 or 2, NR, or NRSO₂ where R is hydrogen or C₁₋₆alkyl. Preferably A is a bond or a group CH₂O, OCH₂, or O.

Suitably A is an optionally substituted phenyl group or an optionallysubstituted 5- or 6-membered heterocyclic ring containing up to threeheteroatoms selected from nitrogen, oxygen or sulphur. Preferably A isthiazolyl, isothiazoly, oxazoly, isoxazolyl, thoadiazoly, triazoly,pyridyl, pyrimidyl or pyrazinyl. Most preferably A is thiazolyl.Optional substitutents when A is a phenyl or a heterocyclic groupinclude those groups R¹ and R² listed above.

The urea moiety can be attached to a carbon or any available nitrogenatom of the ring P², preferably it is attached to a carbon atom.Suitable moieties when the rings P¹ and P² are 5-membered aromaticheterocyclic rings include isothiazolyl, isoxazolyl, thiadiazolyl,oxadiazolyl and triazolyl. Suitable moieties when the rings P¹ and R²are 6-membered aromatic heterocyclic rings include, for example,pyridyl, pyrimidyl or pyrazinyl. Optional substituents for P¹or P²groups include those groups R¹ and R² listed above.

When A is a bond, P¹ is preferably phenyl, pyridyl, pyrimidyl, pyraxinylor pyridazinyl, preferably phenyl or pyridyl, in particular 3-pyridyl.

When A is a chain of 1 to 5 atoms, P¹ is preferably phenyl or pyridyland P² is preferably phenyl or pyridyl, in particular 3-pyridyl.

When A is an optionally substituted phenyl group or an optionallysubstituted 5- or 6-membered aromatic heterocyclic ring, P¹ ispreferably phenyl or pyridyl and P² is preferably phenyl or pyridyl, inparticular 3-pyridyl.

Preferably R¹ is hydrogen or methyl.

Preferably R² is hydrogen, halogen, methyl, CF₃ or OCF₃.

Preferably R³is hydrogen.

Preferably R⁴ is a group of formula (i). Preferably X and Y form part ofa phenyl ring, that is to say one of X or Y is carbon and the other is aCH group or both of X and Y are CH groups. Most preferably R⁴ is a groupof formula (A):

in which R⁶ and R⁷ are defined in formula (i).

Suitably R⁶ and R⁷ groups are independently hydrogen, C₁₋₆ alkyloptionally substituted by one or more fluorine atoms for example CF₃ orC₂F₅, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl C₁₋₆alkoxy, C₂₋₆alkynyl, C₃₋₆ cycloalkyloxy, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₆ alkylthio,C₃₋₆ cycloalkylthio, C₃₋₆ cycloalkyl-C₁₋₆ alkythio, C₁₋₆alkoxy, hydroxy,halogen, nitro, CF₃, C₂F₅, OCF₃, SCF₃, SO₂CF₃, SO₂F, formyl, C₂₋₆alkanoyl, cyano, optionally substituted phenyl or thienyl, NR¹²R¹³,CONR¹²R¹³ or CO₂R¹⁴ where R¹², R¹³ and R¹⁴ are as defined for R¹; or R⁶ad R⁷ form part of an optionally substituted 5- or 6-memberedcarbocyclic or heterocyclic ring. Examples of such rings includecyclopentane and dihydrofuran rings.

Preferably R⁶ is trifluoromethyl or halogen and R⁷ is C₁₋₆ alkoxy, inparticular methoxy, C₁₋₆alkylthio, in particular methylthio or C₁₋₆alkyl in particular methyl.

Suitably n and m are independently 0, 1 or 2. Preferably n and m areboth 1.

Particular compounds of the invention include:

1-[(3-Pyridyl)-3-phenyl carbamoyl]-5-methoxy-6-trifluromethyl indoline,

1-[(4-Pyridyl)-3-phenyl carbamoyl]-5-methylthio-6-trifluoromethylindoline,

1-[(3-Pyridyl)-3-phenyl carbamoyl]-5-methylthio-6-trifluoromethylindoline,

1-[(3-Pyridyl)-4-phenyl carbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[(4-Pyridyl)-4-phenyl carbamoyl]-5-methoxy-6-trifluoromethyl indoline,

1-[(2-Pyridyl)-3-phenyl carbamoyl]-5-methoxy-6-trifluoromethyl indoline,

1-[(4-Methyl-3-(3-Pyridyl)-phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[3-Fluoro-5-(3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[2-Fluoro-5-(3-pyridyl)phenyl carbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-(5-Phenyl pyrid-3-yl carbamoyl)-5-methoxy-6-trifluoromethyl indoline,

1-(5-Phenyl pyrid-3-yl carbamoyl)-5-methylthio-6-trifluoromethylindoline,

1-[5-(3-Pyridyl)-pyrid-3-yl carbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[5-(4-Trifluoromethylphenyl)-pyrid-3-ylcarbamoyl]-5-methopxy-6-trifluoromethyl indoline,

1-[5-(4-Methylphenyl)-pyrid-3yl carbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[5-(2-Thienyl)-pyrid-3-yl carbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[5-(3-Thienyl)-pyrid-3-yl carbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[5-(2-Pyrrolyl)-pyrid-3-yl carbamoyl)-5-methoxy-6-trifluoromethylindoline,

1-[5-(4-Pyridyl)-pyrid-3-yl carbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[2-(3-Pyridyl)-thiazol-4-yl carbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[2-(2-Pyridyl)-thien-5-yl carbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-(3-Fluoro-5-(4-methyl-3-pyridyl)phenylcarbamoyl)-5-methoxy-6-trifluoromethylindoline,

1-(5(2,6-Difluorophenyl)-3-pyridylcarbamoyl-5methoxy-6-trifluoromethylindoline,

6-Chloro-5-methyl-1-(4-methyl-3-(pyrid-3-yl)-phenylcarbamoyl) indoline,

1-(4-Methyl-3-(pyrid-3-yl)phenylcarbamoyl)-5-thiomethyl-6-trifluoromethyl indoline,

1-(3-Fluoro-5-(pyrid-3yl)phenylcarbamoyl)-5-thiomethyl-6-trifluoromethyl-indoline,

1-(4-Choro-3-(pyrid-3-yl)phenylcarbamoyl)-5-methoxy-6-trifluoromethylindoline,

5-Methoxy-1-(5-methyl-(1,2-4-oxadiazol-3-yl)-phenycarbamoyl)-6-trifluoromethylindoline,

1-[4-Methyl-3-(4-methyl-3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[5-Bromo-3-(pyrid-3-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[4-t-Butyl-3-(pyrid-3-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[4-Methoxy-3-(pyrid-3-yl)phenylcarbamoyl]-5-methoxy-6-trifluorormethylindoline,

1-[5-Fluoro-4-methoxy-3-(pyrid-3-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[3-Bromo-4-methyl-5-(3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[3-(4-Isoquinolyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[5-(4-Methyl-3-pyridyl)-pyrid-3-ylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[6-(3-Pyridyl)-pyrid-3-ylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[5-(2-Furyl)-pyrid-3-ylcarbamoyl-5-methoxy-6-trifluoromethyl indoline,

1-[2-(Pyrazinyl)-thoiazol-4-ylcarbamoyl]-5-methoxy-6-trifluoromethyl-indoline,

1-[3-(5-Pyrimidyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl-indoline,

1-[3-(4-Methyl-3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[5-Ethyl-3-(pyrid-3-yl)-phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,

5-Methoxy-1-[5-phenyl-3-(pyrid-3-yl)phenylcarbamoyl]-6-trifluoromethylindoline,

6-Chloro-5-methyl-1-[4-methyl-3-(4-methyl-3-phyridyl)phenylcarbamoyl]indoline,

1-[3-(pyrid-3-ylaminocarbonyl)-phenylcarbamoyl]-5-methoxy-6-trifluoromethyl-indoline,

1-[3-(Pyrid-3-ylaminocarbonyl)-phenylcarbamoyl]-5-methyllthio-6-trifluoromethyl-indoline,

1-[3-(pyrid-4-ylaminocarbonyl)-phenylcarbamoyl]-5-methylthio-6-trifluoromethylindoline,

1-4-(Pyrid-3-ylaminocarbonyl)-phenylcarbamoyl]-5-methylthio-6-thrifluoromethylindoline,

1-[4-(Pyrid-4-ylaminocarbonyl)-phenylcarbamoyl]-5-methylthio-6-trifluoromethylindoline,

1-[3-(3-pyridylcarbonyl-phenylcarbamoyl]- 5-methoxy-6-trifluroomethylindoline,

1-[3-(pyrid-3-yl-aminosulophonyl)-phenylcarbamoyl]-5-methoxy-6-trifluoromethyl-indoline,

5-Methylthio-6-trifluoromethyl-1-[6-(pyridin-3-yloxy)pyridin-3-ylcarbamoyl)]indoline,

5-methoxy-6-trifluoromethyl-1-[6-(pyridin-3-ylcarbamoyl]indoline,

5-Methoxy-6-trifluoromethyl-1-[4-(pyridin-4-ylmethyloxy)phenylcarbamoyl]idoline,

5-Methoxy-6-trifluoromethyl-1-[6-(pyridin-4-ylmethloxy)pyridin-3-ylcarbamoyl]indoline,

5-Methylthio-6-trifluoromethyl-1-[4-(pyrid-4-yl-methylaminocarbonyl)phenyl carbamoyl]indoline,

Trans-5-Methylthio-6-trifluoroemthyl-1-[4-[2-ethenyl-(4-pyridyl)]-phenylcarbamoyl]-indoline,

5-Methylthio-6-trifluoromethyl-1-{4-[2-ethyl(4-pyridyl)phenyl]carbamoyl}indoline,

1-(1-(4-Pyridyl)-5-indolylcarbamoyl)-5-methoxy-6-trifluoromethylindoline,

5-Methoxy-6-trifluoromethyl-1-[4-(pyridin-4-ylthiomethyl)phenylcarbamoyl]indoline,

5-Methoxy-6-trifluromethyl-1-[4-(pyridin-4-ylsulphonylmethyl)phenylcarbamoyl]indoline,

5-Methoxy-6-trifluoromethyl-1-[4-(pyridin-4-ylmethylthio)phenylcarbamoyl]indoline,

5-Methylthio-6-trifluoromethyl-1-[(6-phenoxy)-3-pyridylcarbamoyl]-indoline,

5-Methoxy-6-trifluoromethyl-1-[2-(pyridin-3-yloxy)pyridin-4-ylcarbamoyl)]indoline,

5-Methylthio-6-trifluoromethyl-1-[6-(2-methylpyridin-3-yloxy)pyridin-3-ylcarbamoyl]indoline,

5-Methylthio-6-trifluromethyl-1-[6-(6-methylpyridin-3-yloxy)pyridin-3-ylcarbamoyl]indoline,

5-Methoxy-6-trifluoromethyl-1-[6-(pyridin-3-ylthio)pyridin-3-ylcarbamoyl]indoline,

5-methylthio-6-trifluoromethyl-1-[4-(pyrid-3-ylmethyl)amido phenylcarbamoyl]indoline,

5-Methylthio-6-trifluoromethyl-1-[3-(pyrid-4-ylmethyl)amidophenylcarbamoyl]indoline,

5-Methylthio-6-trifluoromethyl-1-[4-(pyrid-2-ylmethyl)amidophenylcarbamoyl]indoline,

1-(1-(3-Pyridylmethyl)-5-indolycarbamoyl)-5-methoxy-6-trifluoromethylindoline,

1-(1-(4-Pyridylmethyl)-5-indolylcarbamoyl)-5-methoxy-6-trifluoromethylindoline,

1-(1-(3-pyridyl)-5-indolylcarbamoyl)-5-methoxy-6-trifluoromethylindoline,

5-Methylthio-6-trifluoromethyl-1-{3-[2-(3-pyridyl)thiazol-4-yl]phenylcarbamoyl}indoline,

5-Methylthio-6-trifluoromethyl-1-{4-[2-(4-pyridyl-thiazol-4-yl]phenylcarbamoyl}indoline,

5-Methylthio-6-trifluoromethyl-1-{4-[2-(3-pyridyl)-thiazol-4-yl]phenylcarbamoyl}indoline,

1-[4-Fluoro-3-(3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[3-Fluoro-5-(pyrimidin-5-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[4-Chloro-3-(4-methyl-3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[2,3-Dihydro-7-(pyrid-3-yl)benzofuran-5-ylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,

5-Methoxy-6-trifluoromethyl-1-[6-(2-methylpyridin-3-yloxy)pyridin-3-ylcarbamoyl]indoline,

5-Methoxy-6-trifluromethyl-1-[6-(4-methylpyridin-3-yloxy)pyridin-3-ylcarbamoyl]indoline,

and pharmaceutically acceptable salts thereof.

Further preferred compounds are those of examples 83-177 andpharmaceutically acceptable salts thereof.

The compounds of the formula (I) can form acid addition salts withacids, such as conventional pharmaceutically acceptable acids, forexample maleic, hydrochloric, hydrobromic, phosporic, acetic, fumaric,salicylic, citric, lactic, mandelic, tartaric and methanesulphonic.Preferred salts are mesylate salts.

Compounds of formula (I) may also form N-oxides or solvates such ashydrates, and the invention also extends to these forms. When referredto herein, it is understood that the term compound of formula (I)′ alsoincludes these forms.

Certain compounds of formula (I) are capable of existing instereoisomeric forms including enantiomers and the invention extends toeach of these steroisomeric forms and to mixtures thereof includingracemates. The different stereoisomeric forms may be separated one fromthe other by the usual methods, or any given isomer may be obtained bystereospecific or asymmetric synthesis. The invention also extends toany tautomeric forms and mixtures thereof.

The present invention also provides a process for the preparation of acompound of formula (I) or a pharmaceutically acceptable salt thereof,which process comprises:

(a) the coupling of a compound of formula (II);

with a compound of formula (III);

D-R^(4′)  (III)

wherein A, P¹and P² are as defined in formula (I), C and D contain theappropriate functional group(s) necessary to form the moiety —NR^(3′)COwhen coupled, the variables R^(1′), R^(2′), R^(3′) and R^(4′) are R¹,R², R³ and R⁴ respectively, as defined in formula (I), or groupsconvertible thereto, and thereafter optionally and as necessary and inany appropriate order, converting any R^(1′), R^(2′), R^(3′) and R^(4′),when other than R¹, R², R³ and R⁴ respectively to R¹, R², R³ and R⁴,interconverting R¹, R², R³ and R⁴ and forming a pharmaceuticallyacceptable salt thereof; or

(b) the coupling of a compound of formula (IV);

with a compound of formula (V);

wherein P¹, P², R^(1′), R^(2′), R^(3′) and R^(4′) are as defined asabove and E and G contain the appropriate functional group(s) necessaryto form the A moiety when coupled and thereafter optionally and asnecessary and in any appropriate order, converting any R^(1′), R^(2′),R^(3′) and R^(4′), when other than R¹, R², R³ and R⁴ respectively to R¹,R², R³ and R⁴, interconverting R¹, R², R³ and R⁴ and forming apharmaceutically acceptable salt.

Suitable examples of groups C and D include:

(i) C is —N═C═O and D is hydrogen,

(ii) C is —NR^(3′)COL and D is hydrogen,

(iii) C is —NHR^(3′)and D is COL, or

(iv) C is halogen and D is —CONHR^(3′)

wherein R^(3′) is as defined above and L is a leaving group. Examples ofsuitable leaving groups L include halogen such as chloro, bromo,imidazole, phenoxy or phenylthio optionally substituted, for example,with halogen.

Suitable examples of a group R^(2′) which are convertible to R², includealkoxycarbonyl and benzyloxy or para-methoxybenzyloxy which areconverted to the group where R² is hydroxy using conventionalconditions.

Interconversions of R¹, R² and R³ are carried out by conventionalprocedures. For example R¹ halo can be introduced by selectivehalogenation of the ring P¹ using conventional conditions. It should beappreciated that it may be necessary to protect any R¹ to R³ hydrogenvariables which are not required to be interconverted.

Suitable protecting groups and methods for their attachment and removalare conventional in the art of organic chemistry, such as thosedescribed in Greene T. W. ‘Protective groups in organic synthesis’ NewYork, Wiley (1981).

Compounds of formula (II) and (III) may be prepared according to knownmethods or analogeous to known methods, for example using the proceduresdescribed in WO 95/01976. Compounds of formula (II) in which C is NH₂,NO₂ or CO₂H can be prepared by reacting a compound of formula (VI) witha compound of formula (VII):

in which R^(1′), R^(2′), P¹ and P² are as defined in formula (II) and Tand Q contain the appropriate functional groups necessary to form the Agroup. For example

a) when A is a bond, one of T and Q is B(OH)₂, or Sn(BU)₃ and the otheris halogen or OTf (see for example Adv. Het. Chem. 1995, 62 306).

b) when A is a chain, one of T and Q is an acid chloride and the otheris amino, or one of T and Q is hydroxy and the other is chloro orchloromethyl; or

(c) when A is a heterocyclic ring, one of T and Q is a thioamide groupand the other is BrCH₂C═O.

Compounds of formula (III) may be prepared according to known methods oranalogous to known methods, for example

a) from the appropriate aniline via indole formation (Nordlander [JOC,1981, 778] or Sundberg [JOC 1984, 249] routes) followed by reduction ofthe indole ring using sodium cyanoborohydride. It will be appreciatedthat in certain cases a mixture of indoles will be formed which can beseparated at this stage or at a later stage.

b) from the appropriate ortho-methyl nitrobenzene via indole formation(Leimgruber procedure Org Syn Coll vol VII, p34) followed by reductionof the indole ring.

c) by aromatic substitution of a suitably protected indole/indolineprecursor, for example alkylthio groups maybe introduced bythiocyanation of the indoline ring followed by hydrolysis andalkylation, or

d) From the appropriate nitrobenzene via indole formation by aromaticnucleophilic substitution (J.Med. Chem. 1990, 2089) followed byreduction of the indole using NaCNBH₃.

Novel intermediates of formula (III) also form part of the invention.

Suitable examples of reactions of compounds of formulae (IV) and (V) arethose where E and G are the same as T and Q respectively in compounds offormulae (VI) and (VII) above. Compounds of formula (IV) arecommercially available or can be prepared using standard procedures.Compounds of formula (V) can be prepared using standard procedures suchas those outlined in WO 94/04533 or WO 95/01976.

Pharmaceutically, acceptable salts may be prepared conventionally byreaction with the appropriate acid or acid derivative. N-oxides may beformed conventionally by reaction with hydrogen oxide or percarboxylicacids.

Compounds of formula (I) and their pharmaceutically acceptable saltshave 5HT_(2B/2C) receptor antagonist activity and are believed to be ofpotential use of the treatment or prophylasis of CNS disorders such asanxiety, depression, epilepsy, obsessive compulsive disorders, migraine,Alzheimers disease, sleep disorders, feeding disorders such as anorexiaand bulimia, panic attacks, withdrawal from drug abuse such as cocaine,ethanol, nicotine and benzodiazepines, schizophrenia, and also disordersassociated with spinal trauma and/or head injury such as hydrocephalus.Compounds of the invention are also expected to be of use in thetreatment of certain GI disorders such as IBS as well as microvasculardiseases such as macular oedema and retinopathy.

Thus the invention also provides a compound of formula (I) or apharmaceutically acceptable salt thereof, for use as a therapeuticsubstance, in particular in the treatment or prophylaxis of the abovedisorders.

The invention further provides a method of treatment or prophylaxis ofthe above disorders, in mammals including humans, which comprisesadministering to the sufferer a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides the use of a compound offormula or a pharmaceutically acceptable salt thereof in the manufactureof a medicament for the treatment or prophylaxis of the above disorders.

The present invention also provides a pharmaceutical composition, whichcomprises a compound of formula (I) or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

A pharmaceutical composition of the invention, which may be prepared byadmixture, suitably at ambient temperature and atmospheric pressure, isusually adapted for oral, parenteral or rectal administration and, assuch, may be in the form of tablets, capsules, oral liquid preparations,powders, granules, lozenges, reconstitutable powders, injectable orinfusable solutions or suspensions or suppositories. Orallyadministrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form,and may contain conventional excipients, such as binding agents,fillers, tabletting lubricants, disintegrants and acceptable wettingagents. The tablets may be coated according to methods well known innormal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending argents, emulsifying agents,non-aqueous vehicles (which may include edible oils), preservatives,and, if desired, conventional flavourings or colourants.

For parenteral administration, fluid unit dosage forms are preparedutilising a compound of the invention or pharmaceutically acceptablesalt thereof and a sterile vehicle. The compound, depending on thevehicle and concentration used, can be either suspended or dissolved inthe vehicle. In preparing solutions, the compound can be dissolved forinjection and filter sterilised before filling into a suitable vial orampoule and sealing. Advantageously, adjuvant such as a localanesthetic, preservatives and buffering agents are dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved, andsterilization cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspension in a sterilevehicle. Advantageously, a surfactant or wetting agent is included inthe composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from10 to 60% by weight, of the active material, depending on the method ofadministration.

The dose of the compound used in the treatment of the aforementioneddisorders will vary in the usual way with the seriousness of thedisorders, the weight of the sufferer, and other similar factors.However, as a general guide suitable unit doses may be 0.05 to 1000 mg,more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; and such unitdoses may be administered more than once a day, for example two or threea day, so that the total daily dosage is in the range of about 0.5 to100 mg; and such therapy may extend for a number of weeks or months.

When administered in accordance with the invention, no unacceptabletoxicological effects are expected with the compounds of the invention.

The following Descriptions and Examples illustrate the preparation ofcompounds of the invention.

Description 1 6-Trifluoromethylindoline (D1)

6-Trifluoromethylindole¹ (5.27 g, 28.5 mmol) in glacial acetic acid (50ml) was treated with sodium cyanoborohydride (3.60 g, 57.0 mmol)portionwise at room temperature with stirring. After 3 h at roomtemperature the reaction mixture was diluted with water (100 ml) andbasified with 40% aqueous NaOH with cooling. The mixture was thenextracted with dichloromethane (3×150 ml) and the combined extracts weredried (Na₂SO₄) and evaporated to give the title compound (4.83 g, 91%)as a brown solid.

¹H NMR (CDCl₃) δ: 3.07 (2H, t, J=8), 3.62 (2H, t, J=8), 6.80 (1H s),6.92 (1H, d, J=8), 7.15 (1H, d, J=8).

1. A. N. Tischler and T. J. Lanza, Ter. Lett, 1986, 26, 1653.

Description 2 5-Thiocyanato-6-trifluoromethylindoline (D2)

A mixture of 6-trifluoromethylindoline (D1) (9.7 g, 52 mmol) andpotassium thiocyanate (10.09 g, 104 mmol) in methanol (200 ml) wastreated with a solution of bromine (2.82 ml, 55 mmol) in methanol (35ml) dropwise over 0.5 h at −5-0° C. The reaction mixture was allowed towarm to room temperature and stirred overnight then evaporated todryness. The residue was partitioned between aqueous K₂CO₃ (100 ml) anddichloromethane (3×100 ml). The combined extracts were dried (Na₂SO₄)and evaporated and the residue chromatographed, on silica using 2-30%ethyl acetate/petroleum ether as eluant to afford the title compound(9.1 g, 72%) as a yellow solid.

¹H NMR (CDCl₃) δ: 3.12 (2H, t, J=8), 3.72 (3H, t, J=8), 4.23 (1H, br s),6.89 (1H, s), 7.50 (1H, s).

Description 3 Di[5-(6-trifluoromethylindolinyl)]disulphide (D3)

The thiocyanate (D2) (28.5 g, 0.116 mol) in dioxane (200 ml) and water(100 ml) was treated with aqueous ammonia (880, 200 ml) at 90° C. for 1h. The mixture was cooled and evaporated to give a residue which waspartitioned between water (300 ml) and dichloromethane (4×300 ml). Thecombined extracts were dried (Na₂SO₄) and evaporated to give the titlecompound (25.5 g, 100%) as a yellow solid.

¹H NMR(CDCl₃) δ: 3.03 (2H, t, J=8), 3.67 (2H, t, J=8), 4.00 (1H, br s),6.80 (1H, s), 7.49 (1H, s).

Description 4 Di-[5-(1-acetyl-6-trifluoromethylindolinyl)]disulphide(D4)

The disulphide (D3) (26 g, 0.119 mol) in dichloromethane (300 ml) andtrimethylamine (47.3 ml, 0.339 mol) was treated dropwise with a solutionof acetic anhydride (22.5 ml, 0.238 mol) in dichloromethane (50 ml) at0° C. The mixture was allowed to warm to room temperature, stirred for 1h then poured into 2.5 M aqueous HCl (400 ml). The organic layer wasseparated and the aqueous was further extracted with dichloromethane(200 ml). The combined organic extracts were dried (Na₂SO₄) andevaporated to dye the title compound (29.1 g, 94%) as a yellow solid.

¹H NMR (CDCl₃) δ: 2.22 (3H s), 3.21 (2H, t), 4.10 (2H, t), 7.68 (1H, s),8.47 (1H, s).

Description 5 1-Acetyl-5-mercapto-6-trifluoromethylindoline (D5)

A mixture of the diacetyl disulphide (D4) (28.5 g, 54.8 mmol),triphenylphosphine (20.85 g, 79.5 mmol) and conc. aqueous HCl (1 ml) indioxane, (300 ml) and water (75 ml) was heated at reflux. for 1.5 h. Thereaction mixture was cooled and evaporated to a residue which waspartitioned between dichloromethane (300 ml) and 1% aqueous NaOH (300ml). The organic phase was further extracted with 1% aqueous NaOH (200ml) and the combined aqueous fractions carefully actified and extractedwith dichloromethane (3×300 ml). The combined organic extracts weredried (Na₂SO₄) and evaporated to afford the title compound (26 g, 91%)as a yellow solid.

1H NMR (CDCl₃) δ: 2.24 (3H, s), 3.20 (2H, t), 3.68 (1H, M), 4.11 (2H t),7.22 (1H, s), 8.51 (1H, s).

Description 6 1-Acetyl-5-methylthio-6-trifluoromethylindoline (D6)

A mixture of the thiol (D5) (26 g, 99 mmol), anhydrous K₂CO₃ (15.12 g,109 mmol) and indomethane (18.6 ml, 300 mmol) in dry DMF (100 ml) washeated at 80° C. for 1 h. The reaction mixture was cooled, evaporated invacuo and partitioned between water (200 ml) and dichloromethane (3×200ml). The combined organics were washed with water (400 ml), dried (Na₂S0₄) and evaporated to yield the title compound (26.3 g, 97%) as a yellowoil.

1H NMR (CDCl₃) δ: 2.22 (3H, s), 2.49 (3H, s), 3.24 (2H, t, J=8), 4.12(2H, t, J=8), 7.23 (1H, s), 8.51 (1H, s).

Description 7 5-Methylthio-6-trifluoromethylindoline (D7)

Method (a)

The acetyl indoline (D6) (26.3 g, 95 mmol) was treated with NaOH (30 g,750 ml) in water (150 ml) and ethanol (200 ml) at reflux for 1.5 h. Thereaction mixture was cooled, diluted with water (200 ml) and most of theethanol evaporated in vacuo. The remaining mixture was extracted withdichloromethane (3×200 ml) and the combined extracts were dried (Na₂SO₄)and evaporated to afford the title compound (21.9 g, 99%) as a yellowoil.

¹H NMR (CDCl₃) δ: 2.41 (3H, s), 3.07 (2H, t), 3.63 (2H, t), 3.90 (1H, brs), 6.88 (1H s), 7.30 (1H, s).

Method (b)

A stirred solution of potassium thiocyanate (38.6 g, 0.39 mol) inmethanol (470 ml) at −2° C. under argon was treated dropwise over 10minutes with bromine (10.3 ml, 0.195 mol) giving a yellow precipitate.The reaction mixture was stirred at 0° C. for a further 15 minutes, thentreated with a solution of 6-trifluoromethylindoline (D1) (33.2 g, 0.177mol) in methanol (320 ml) and allowed to warm to room temperature andstir for 4 h. A solution of potassium hydroxide (49.5 g, 0.88 mol) inwater (300 ml) was added in one portion, causing the temperature to riseto 43°C. and a brown solution to be produced. The mixture was stirred at43-45° C. for 25 minutes, then cooled to 12° C. and cremated withindomethane (10.9 ml, 0.177 mol). The resulting mixture was allowed towarm to room temperature and stirred for 1.5 h, then concentrated invacuo to approx. 350 ml volume. The residual aqueous mixture wasextracted with dichloromethane (2×400 ml) and the combined extract dried(Na₂SO₄) and concentrated in vacuo to give a brown oil (43 g), which waschromatographed on silica gel eluting with dichloromethane to afford thetitle compound (D7) as a light brown solid (25.3 g, 61%) with spectralproperties identical to those described above.

Description 8 1-Methoxy-4-nitro-2-trifluoromethylbenzene (D8)

Sodium (11.78 g, 0.512 mol) was dissolved in dry methanol (11) and tothe resulting solution was added a solution of1-chloro-4-nitro-2-trifluoromethyl-benzene (96.22 g, 0.427 mol) inmethanol (100 ml). The reaction mixture was refluxed for 3 h then cooledand evaporated in vacuo. The residue was partitioned between water (500ml) and dichloromethane (3×400 ml). The combined organic extracts weredried (Na₂SO₄) and evaporated to give the title compound (93.76 g, 99%)as a white solid.

¹H NMR (CDCl₃) δ: 4.05 (3H, s), 7.12 (1H, d), 8.45 (1H, dd), 8.52 (1H,d).

Description 9 (5-Methoxy-2-nitro-4-trifluoromethylphenyl)acetonitrile(D9)

A mixture of 1-methoxy-4-nitro 2-trifluoromethylbenzene (D8) (93 g,0.421 mol) and 4-chlorophenoxyacetonitrile (77.55 g, 0.463 mol) in dryDMF (500 ml) was added dropwise over 0.75 h to a stirred solution ofKO^(t)Bu (103.85 g, 0.927 mol) in dry DMF (400 ml) at −10° C. Aftercomplete addition the resulting purple solution was maintained, at −10C. for 1 h then poured into a mixture of ice/water (1.51) and 5 Maqueous HCl (1.5 l). The resulting mixture was extracted withdichloromethane (3×1 l). The combined extracts were washed with water (3l), dried (Na₂SO₄) and evaporated under reduced pressure. The residuewas chromatographed on silica using 10-40% ethyl acetate/petroleum etheras eluant to give the crude product which was recrystallised from ethylacetatelpetroleum ether to afford the title compound (85.13 g, 78%) as awhite solid. Mp 103-104° C.

¹H NMR (CDCl₃) δ: 4.10 (3H, s), 4.37 (2H, s), 7.34 (1H, s), 8.53 (1H,s).

Description 10 5-Methoxy-6-trifluoromethylindole (D10)

(5-Methoxy-2-nitro-4-trifluoromethylphenyl)acetonitrile (D9) (85 g,0.327 mol) in ethanol/water (9:1, 1.6 l) and glacial acetic acid (16 ml)was hydrogenated over 10% palladium on carbon (50 g) at 50 psi for 0.5 hat room temperature. The reaction mixture was filtered and evaporated invacuo. The residue was partitioned between aqueous K₂CO₃ (1 l) anddichloromethane (2×1 l) and the combined organic extract was dried(Na₂SO₄) and evaporated to afford the title indole (67.63 g, 96%) as agrey solid.

¹H N-MR (CDCl₃) δ: 3.94 (3H, s), 6.53 (1H, m), 7.21 (1H, s), 7.32 (1H,m), 7.64 (1H, s), 8.25 (1H, br s).

Description 11

5-Methoxy-6-trifluoromethylindoline (D11)

The indole (D10) (67.63 g, 0.315 mol) was treated with sodiumcyanoborohydride (40 g, 0.637 mol) in glacial acetic acid (500 ml) as inthe method of Description 1 to afford the title indoline (67.73 g, 99%)as an off-white solid

¹H NMR (CDCl₃) δ: 3.07 (2H, t), 3.58 (2H t), 3.67 (1H, br s), 3.83 (3H,s), 6.83 (1H, s), 6.88 (1H, s).

Description 12 3-(4-Pyridyl) aniline (D12)

3-Bromoaniline (0.24 ml, 2.2 mmol) and sodium carbonate (0.70 g, 6.6mmol) were suspended in a mixture of 1,2-dimethoxyethane (16 ml) andwater (4 ml). The reaction mixture was then treated with 4-pyridylboronic acid (0.27 g, 2.2 mmol), and flushed with Argon. Tetrakis(triphenylphosphine)-palladium (0) (0.35 g) was then added, and themixture was heated to reflux under Argon for 24 hours. The reactionmixture was allowed to cool after which it was partitioned betweendichloromethane and water. The aqueous layer was again extracted withdichloromethane. The combined extracts were then dried (Na₂SO₄) andconcentrated in vacuo to afford a pale yellow solid (0.35 g). This waschromatographed on silica gel eluting with ethyl acetate to afford thetitle compound as a white solid (0.15 g, 41%).

¹H NMR (200 MHz, CDCl₃) δ(ppm): 8.63 (dm, 2H), 7.45 (dm, 2H), 7.35 (t,1H), 7.0 (dm, 1H), 6.91(m, 1H), 6.75 (dm, 1H), 3.75 (b, 2H)

Description 13 3-(3-Pyridyl)aniline (D13)

A mixture of 3-bromopyridine (2.9 ml, 4.74 g, 30 mmol), 3-aminophenylboronic acid (4.63 g, 30 mmol), sodium carbonate (10 g, 90 mmol) andtetrakis (triphenylphosphine) palladium (0) (0.9 g) in1,2-dimethoxyethane—water (150 ml-50 ml) was heated to reflux underargon for 12 h. The mixture was concentrated then partitioned betweenethyl acetate/dilute brine. The organic extract was dried and evaporatedaffording a brown gum (6 g). Chromatography on silica eluting with 50%ethyl acetate—60/80 petroleum ether then ethyl acetate afforded theproduct as a yellow crystalline solid (4.8 g, 95%).

¹H NMR (200 MHz, CDCl₃) 3.8 (2H, 6s), 6.70 (1H, dm), 6.85 (1H, m), 6.95(1H, m), 7.25 (1H, t), 7.35 (1H, m) 7.85 (¹H, m), 8.60 (1H, dd), 8.85(1H, d).

Description 14 1-(5-Bromo-pyrid-3-ylcarbamoyl)-5-methoxy-6-trifluromethyl-indoline (D14)

A solution of 5-bromo-pyrid-3-yl acryl azide (3.16 g, 13.9 mmol) intoluene (500 ml) was heated to reflux under argon for 1 h. The solutionwas allowed to cool to room temperature then added to a solution of5-methoxy-6-trifluoro-methyl indoline (2.7 g, 12.5 mmol) indichloromethane (200 ml). The mixture was set aside in the fridge for 1h, then filtration and drying afforded the title compound as a whitesolid (4.62 g, 89%), mp 220-222° C.

¹H NMR (D6-DMSO) 3.30 (2H, t, J), 3.85 (3H, S), 4.20 (2H, t), 7.20 (1H,S), 8.10 (1H, S), 8.35 (2H, m), 8.75 (1H, S), 8.95 (1H, S).

Description 15 2-(3-Pyridyl)-thiazole-4-carbonyl azide (D15)

A suspension of 2-(3-pyridyl)-thiazole-4-carboxylic acid (0.824 g, 4mmol) in dichloromethane-chloroform (30 ml-15 ml) was treated withtrimethylamine (0.75 ml, 0.5 g, 5 mmol) and then iso-butyl chloroformate(0.65 ml, 0.68 g, 5 mmol). After 1 h the mixture was evaporated todryness and the residue suspended in THF (30 ml) and a solution ofsodium azide (0.46 g, 7 mmol) in water (10 ml) was added. After 1 h, themixture was concentrated (rotary evaporator) and partitioned betweendichloromethane and brine. The organic extract was washed withhalf-saturated brine, dried, and evaporated. Trituration with petroleumether, filtration, and drying in vacuo (CAUTION—no heating) afforded thetitle compounds as a brown solid (0.37 g, 40%).

Description 16 2-(2-Pyridyl)-thiophene-5-carbonyl azide (D16)

This was prepared in 45% yield by the same method as for Description 15.

Description 171-(3-Fluoro-5-indophenylcarbamoyl)-5-methoxy-6-trifluoromethylindoline(D17)

A mixture of 3-fluoro-5-indoaniline (0.47 g, 1.98 mmol) and1,1′-carbonyl diimidazole (0.33 g, 2 mmol) in dichloromethane (40 ml)was stirred at room temperature for 1 h, then evaporated to dryness. Tothe residue was added dimethylformamide (DMF,10 ml) and a solution of5-methoxy-6-trifluoromethylindoline (D11, 0.44 g, 2 mmol) in DMF (5 ml).The mixture was heated at 80° C. overnight, then cooled and poured intowater. The precipitate was filtered off, washed with water and dried.The crude product was chromatographed on silica gel and eluted withdichloromethane. Eluted product was recrystallised from dichloromethaneto give the tide compound (0.38 g, 40%), Mp. 221-4° C.

¹H NMR (d₆DMSO) δ: 3.27 (2H, t, J=8), 3.84 (3H, s), 4.15 (2H, t, J=8),7.20 (1H, s), 7.27 (1H, d, J=7), 7.57 (1H, d, J=12), 7.84 (1H, s), 8.10(1H, s), 8.78 (1H, s). MS (EI) m/z=480 (M⁺), C₁₇H₁₃N₂O₂F₃I requiresM=480

Description 18 Ethyl 5-(2,6-difluorophenyl)nicotinate (D18)

A mixture of (2,6-difluorophenyl)tributyltin (1.18 g, 2.9 mmol), ethyl5-bromonicotinate (0.69 g, 3 mmol) and tetrakis (triphenylphosphine)palladium (0) (0.10 g) in xylene (10 mL) was heated under reflux for 24h, then cooled, filtered and evaporated. The residue was chromatographedon silica gel eluted with 20% ethyl acetate/petrol to give the titlecompound (0.64 g, 84%).

¹H NMR (CDCl₃) δ: 1.43 (3H, t, J=7), 4.44 (2H, q, J=7), 7.06 (2H, t,J=7), 7.39 (1H, quintet, J=7), 8.42 (1H, s), 8.88 (1H, s), 9.23 (1H, s)

MS (API): m/z=264 (MH⁺), C₁₄H₁₁NO₂F₂ requires M+1=264

Description 19 5-(2,6-Difluorophenyl)nicotinoyl Hydrazide (D19)

A mixture of ester (D18, 0.64 g, 2.4 mmol) and 98% hydrazine hydrate (1mL) in methanol (10 mL) was heated under reflux overnight, then cooledin ice. The precipitate was filtered off. The filtrate was evaporatedand the residue was triturated with water before combining with theinitial precipitate. The crude product was washed with ether and driedin vacuo to give the title compound (0.50 g, 84%).

¹H NMR (d₆DMSO) δ: 4.60 (2H, s), 7.29 (2H, t, J=7), 7.57 (1H, quintet,J=7), 8.28 (1H, s), 8.80 (1H, s), 9.03 (1H, s), 10.05 (1H, s).

MS (API): m/z=250 (MH⁺), C₁₂H₉N₃OF₂ requires M+1=250

Description 20 5-(2,6-Difluorophenyl)nicotinoyl azide (D20)

To a suspension of hydrazide (D19, 0.50 g, 1.99 mmol) in concentratedhydrochloric acid (3 mL) and water (2 mL) at −5° C. was added dropwise asolution of sodium nitrite (0.14 g, 2.0 mmol) in water (2ml). Themixture was stirred at −5° C. for 0.5 h, then a solution of potassiumcarbonate (2.3 g) in water (25 ml) was added cautiously. The precipitatewas filtered off, washed with water and dried in vacuo at roomtemperature to give the title compound (0.48 g, 93%).

¹H NMR (CDCl₃) δ: 7.05 (2H, t, J=7), 7.40 (1H, quintet, J=7), 8.41 (1H,s), 8.93 (1H, s), 9.22 (1H, s)

MS (API) 261 (MH⁺), 233 (MH⁺−N₂)

Description 21 Phenyl N-(3-Bromo-5-(pyrid-3-yl)phenyl)carbamate (D21)

The title compound was prepared from 3-Bromo-5-(pyrid-3-yl)aniline usingthe method of Description 67.

¹H NMR 250 MHz CDCl₃δ: 7.1-7.9 (m, 9H), 8.6-8.7 (br, 1H, Ar), 8.8-8.9(br, 1H, Ar)

Description 22 Phenyl N-[4-Butyl-3-(pyrid-3-yl)phenyl]carbamate (D22)

The title compound (0.18 g, 68%) was prepared from4-t-butyl-3-(pyrid-3-yl)aniline (0.17 g, 0.00077 mole) using the methodof Description 67.

¹H NMR (200 MHz, CDCl₃) δ: 1.18 (9H, s), 7.02-7.65 (11H, m), 8.49-8.62(2H, m)

Description 23 Phenyl N-[4-Methoxy-3-(pyrid-3-yl)phenyl]carbamate (D23)

The title compound (0.48 g, 75%) was prepared from4-methoxy-3-(pyrid-3-yl)aniline (0.40 g, 0.002 mole) using the method ofDescription 67.

¹H NMR (200 MHz, CDCl₃) δ: 3.80 (3H, s), 6.90-7.57 (10H, m), 7.88 (1H,dt), 8.56 (1H, dd), 8.78 (1H, d)

Description 24 PhenylN-[5-Fluoro-4-methoxy-3-(pyrid-3-yl)phenyl]carbamate (D24)

The title compound (0.48 g, 79%) was prepared from5-fluoro-4-methoxy-3-(pyrid-3-yl)aniline (0.40 g, 0.0018 mole) using themethod of Description 67.

¹H NMR (200 MHz, CDCl₃) δ: 3.75 (3H, s), 7.01-7.67 (8H, m), 7.82-8.08(2H, m), 8.64 (1H, d), 8.80 (1H, s).

Description 251-(3,5-Dibromo-4-methylphenylcarbamoyl)-5-methoxy-6-trifluoromethylindoline(D25)

The title compound was prepared by the method of Example 1, from3,5-dibromo-4-methylaniline (2.64 g, 10 mmol), 1,1′-carbonyldiimidazole(1.64 g, 10 mmol) and 5-methoxy-6-trifluoromethylindoline (D11) (2.2 g,10 mmol). Crude product was recrystallised from DMSO/water and washedwith methanol and ether, to give the title compound (2.64 g, 52%),mp>250° C.

NMR (d₆-DMSO) δ: 2.43 (3H, s), 3.26 (2H, t, J=8), 3.84 (3H, s), 4.14(2H, t, J=8), 7.20 (1H, s), 7.96 (2H, s), 8.10 (1H, s), 8.72 (1H, s).

MS (API) 507 (MH⁺, ⁷⁹Br₂), 509 (MH⁺, ⁷⁹Br⁸¹Br), 511 (MH⁺, ⁸¹Br₂)

Description 261-[5-Bromo-(3-pyridylcarbamoyl)]-5-methoxy-6-trifluoromethyl indoline(D26)

5-Bromo-3-pyridylcarbonylazide (3.7 g, 16 mmoles) was heated underreflux in dry toluene (100 ml) for 1 hr. After cooling the resultingsolution of isocyanate was treated with a solution of5-methoxy-6-trifluoromethyl indoline (D11) (3.5 g, 16 mmoles) indichloromethane (600 ml) and stirred overnight. The mixture wasconcentrated in vacuo and the residue triturated with diethyl ether.Filtration and washing with more diethyl ether gave the title compound(D26) (5.4 g, 81%).

¹H NMR (DMSO-d⁶) δ: 3.30 (2H, t, J=8 Hz), 3.83 (3H, s), 4.18 (2H, t, J=8Hz), 7.20 (1H, s), 8.10 (1H, s), 8.30-8.35 (1H, m), 8.71 (1H, s), 8.92(1H, s)

Description 27 Phenyl N-[6-(Pyrid-3-yl)pyrid-3-yl]carbamate (D27)

The title compound was prepared as in the method of description 67 fromthe corresponding aniline. This gave the title compound (0.66 g, 100%)

M.S. (API) found m/z 292 (MH⁺), C₁₇H₁₃N₃O₂ requires 292

Description 28 Phenyl-N-[3-(4-methylpyrid-3-yl)phenyl]carbamate (D28)

The title compound was prepared as in the method of description 67 fromthe corresponding aniline. This gave the title compound (0.8 g, 100%)

NMR (CDCl₃) δ: 2.29 (3H, s), 7.10-7.40 (11H, m), 8.42-8.49 (2H, m)

Description 29 3-(5-Pyrimidyl)-aniline (D29)

This was prepared from 5-bromopyrimidine and 3-aminophenyl boronic acidin 84% yield by the same method as for Description 12.

¹H NMR (CDCl₃) 3.80 (2H, bs), 6.80 (1H, dd), 6.90 (1H, m), 7.00 (1H, d),7.30 (2H, m), 8.95 (2H, s), 9.20 (1H, s).

Description 30 Phenyl N-[3-ethyl-5-(pyrid-3-yl)phenyl]carbamate (D30)

The title compound (0.276 g, 0.87 mmol) was prepared by the methodologyof description 67, using 3-ethyl-5-(pyrid-3-yl)aniline, phenylchloroformate (0.13 ml, 0.96 mmol) and triethylamine (0.13 ml, 0.96mmol) in dichloromethane (10 ml)

¹H NMR 250 MHz CDCl₃ δ: 8.78 (s, 1H, Ar), 8.51 (m, 1H, Ar), 7.08-7.92(m, 5H, Ar), 2.51 (t, 2H, CH₂), 1.20 (q, 3H, Me)

Description 31 Phenyl N-[5-phenyl-3-(pyrid-3-yl)phenyl]carbamate

The title compound (0.289 g, 100%) was prepared by methodology ofdescription 67 using 5-phenyl-3-(pyrid-3-yl)aniline (0.194 mg, 0.79mmol), phenyl chloroformate (0.12 ml, 0.87 mmol) and triethylamine (0.12ml, 0.81 mmol) in DCM (10 ml)

¹H NMR 250 MHz CDCl₃ δ: 8.92 (br, 1H, Ar), 8.65 (d, 1H, Ar), 7.95 (d,1H, Ar), 7.82 (s, 1H, Ar), 7.72-7.12 (m, 8H, Ar)

Description 32 3-(3-Nitrobenzoylamino)-pyridine

A solution of 3-aminopyridine (2 g, 20 mmol) in tetrahydrofuran (100 ml)was treated at 0° C. with triethylamine (3ml, 2.2 g, 2.2 mmol) and thena solution of 3-nitrobenzoyl chloride (3.7 g, 20 mmol) intetrahydrofuran (50 ml). After 0.5 h the reaction mixture was dilutedwith water (400 ml) and set aside in the fridge for 3 days. Fitrationand drying afforded the title compound as a purple crystalline solid(4.82 g, 99%).

¹H NMR (D6-DMSO) 7.40 (1H, m), 7.85 (1H, t, J 8Hz), 8.20 (1H, d, J 8Hz), 8.30-8.50 (3H, m), 8.80 (1H, s), 8.95 (1H, d, J 2 Hz).

Description 33 3-(3-Aminobenzoylamino)-pyridine

A solution of 3-(3-nitrobenzoylamino)-pyridine (2 g, 8.23 mmol) inethanol (200 ml) was treated with 10% palladium on charcoal (0.5 g) andhydrogenated at atmospheric pressure for 4 h. Filtration and evaporationafforded the product as a white solid (1.51 g, 86%).

¹H NMR (D6-DMSO) 5.40 (2H, bs), 6.75 (1H, d J 8 Hz), 7.0-7.2 (3H, m),7.40 (1H, m), 8.15 (1H, d, J 8 Hz), 8.30 (1H, m), 8.90 (1H, d J 2 Hz).

Description 34 5-Methylthio-6-trifluoromethyl-1-(3-ethoxycarbonyl phenylcarbamoyl)indoline

To a stirred solution of carbonyl diimidazole (1.78 g, 11 mmol) indichloromethane (20 ml) was added dropwise a solution of ethyl 3-aminobenzoate (1.65 g, 10 mml) in dichloromethane (20 ml). After 1 hour thereaction mixture was evaporated under reduced pressure before beingtreated with 5-methylthio-6-trifluoromethyl indoline (2.33 g, 10 mmol)and dimethylformamide (30 ml) and heated to 100° C. After 1 hour thereaction mixture was cooled and water added forming a yellowprecipitate. This was filtered and dried to give the product as a yellowsolid (4.19 g, 99%), m.p. 195-7° C.

¹H NMR (DMSO) δ: 8.85 (1H, s); 8.2 (2H, d, J6 Hz); 7.9 (1H, d, J7 Hz);7.6 (1H, d, J7 Hz); 7.4 (2H, t, J6 Hz); 4.3 (2H, q, J7 Hz); 4.2 (2H, t,J8 Hz); 3.25 (2H, t, J8 Hz); 2.5 (3H, s); 1.3 (3H, t, J7 Hz).

Description 35 5-Methylthio-6-trifluoromethyl-1-(4-ethoxycarbonyl phenylcarbamoyl) indoline

This was made in the same manner as Description 34 using ethyl-4-aminobenzoate to give the product as a yellow solid (3.948 g, 93%), m.p.>200°C.

¹H NMR (DMSO) δ: 8.95 (1H, s); 8.2 (1H, s); 7.9 (2H, d, J7 Hz); 7.75(2H, d, J7 Hz); 7.4 (1H, s), 4.2 (4H, m); 3.25 (2H, t, J8 Hz); 2.5 (3H,s); 1.3 (3H, t, J7 Hz)

Description 36 5-Methylthio-6-trifluoromethyl-1-(3-carboxy phenylcarbamoyl)indoline

To a suspension of 5-methylthio-6-trifluoromethyl-1-(3-ethoxy carbonylphenyl carbamoyl) indoline (3 g, 7.1 mmol) in ethanol (30 ml) was addedaqueous sodium hydroxide solution (5M) (7.1 ml, 35.5 mmol) and heatedgently for 2 hours. It was then allowed to cool and acidified withaqueous hydrochloric acid (5M) forming a white precipitate which wasfiltered and dried to yield the product as a white solid (2.324 g, 83%),mp>200° C.

Description 37 5-Methylthio-6-trifluoromethyl-1-(4-carboxy phenylcarbamoyl) indoline

This was made in the same manner as Description 36 using5-methylthio-6-trifluoromethyl-1-(4-ethoxycarbonyl phenyl carbamoyl)indoline to give the product as a pale green solid (2.455 g, 88%),mp>200° C.

¹H NMR (DMSO) δ: 1.27 (1H, s); 8.9 (1H, s); 8.2 (1H, s); 7.9 (2H, d, J7Hz); 7.7 (2H, d, J7 Hz); 7.4 (1H, s); 4.2 (2H, t, J8 Hz); 3.75 (2H, t,J8 Hz); 2.5 (3, s)

Description 38 3-(Pyrid-3-ylaminosulphonyl)-nitrobenzene

To a stirred solution of 3-aminopyridine (2 g, 21.3 mmol) in pyridine(100 ml) was added 3-nitrobenzene sulphonyl chloride (4.43 g, 20 mmol)and the mixture was heated to 50° C. for 3 hours. After cooling it waspartitioned between ethyl acetate and water and the organic washed withwater (×2) and half saturated aqueous sodium chloride solution,separated, dried and evaporated to give a crude yield of 4.96 g. It wasthen triturated with dichloromethane and sonicated for 0.25 hours beforebeing filtered and dried to give the product as a pink solid (4.279 g,72%)

¹H NMR (DMSO) δ: 10.9 (1H, s); 8.45 (2H, d, J7 Hz); 8.3 (2H, s); 8.15(1H, d, J7 Hz); 7.9 (1H, t, J7 Hz); 7.55 (1H, d, J7 Hz); 7.3 (1H, q, J5Hz).

Description 39 3-(Pyrid-3-ylaminosulphonyl)-aminobenzene

To a solution of 3-(pyrid-3-ylaminosulphonyl)-nitrobenzene (4.279 g,15.3 mmol) in ethanol (500 ml)/dimethylformamide (50 ml) was added 10%palladium catalyst on charcoal (1 g) and the reaction mixture washydrogenated at atmospheric pressure for 2 hours. The reaction mixturewas then filtered through kieselguhr before being evaporated underreduced pressure to give the product as a white solid (3.749 g, 98%) 7.3(1H, q, 5 Hz); 7.15 (1H, t, J7 Hz); 6.95 (1H, s); 6.8 (1H, d, J7 Hz);6.7 (1H, d, J7 Hz); 5.6 (2H, s)

Description 40 3-(3-Nitrobenzoyl)pyridine

The title compound (1.55 g, 25%) was prepared using the method ofLanghals et al (Liebigs Ann. Chem. 1982, 930-949), and purified by flashcolumn chromatography on silica gel, eluting with 30% ethyl acetate60-80° petroleum ether.

¹H NMR (200 MHz, CDCl₃) δ: 7.40-7.60 (1H, m); 7.75 (1H, t), 7.98-8.23(2H, m), 8.50 (1H, dd), 8.59-8.70 (1H, m), 8.90 (1H, dd), 9.01 (1H, d)

Description 41 3-(3-Aminobenzoyl)pyridine

3-(3-Nitrobenzoyl)pyridine (1.55 g, 0.006 mole) was suspended in ethanol(35 ml) and treated portionwise with a solution of tine (II) chloride(4.56, 0.024 mmole) in conc. HCl (7 ml). The reaction mixture wasstirred at 50° C. for 2 hours. After allowing to cool to roomtemperature, water (50 ml) was added and the mixture basified with 10%aqueous sodium hydroxide, extracted into ethyl acetate, dried (Na₂SO₄)and evaporated in vacuo to afford the title compound (1.14 g, 85%) as apale oil

¹H NMR (200 MHz; CDCl₃) δ: 3.90 (2H, s); 6.81-7.03 (1H, m), 7.03-7.20(2H, m), 7.28 (1H, t), 7.39-7.59 (1H, m), 8.14 (1H, dd), 8.80 (1H, dd),9.01 (1H, s)

Description 42 Trans-4-[2-ethenyl-(4-pyridyl)]-nitrobenzene (D42)

A solution of (4-nitrobenzyl)triphenylphosphonium bromide (32 g, 66 mmolin ethanol (100 ml) was treated with sodium methoxide (3.6 g, 66 mmol).After 0.75 h pyridine-4-carboxaldehyde (5.04 ml, 52.8 mmol) was addedand the mixture stirred for 16 h. The mixture was subjected to an ethylacetate/dilute brine workup. Drying, evaporation and chromatographyafforded the product as an equal mixture of isomers. Recrystallizationfrom ethyl acetate petroleum ether afforded the title compound (singleisomer) as a yellow solid (2.72 g, 17%).

¹H NMR (D6-DMSO) 7.50 (1H, d), 7.65 (2H, d), 7.70 (1H, d), 7.95 (2H, d),8.30 (2H, d), 8.65 (2H, d).

Description 43 Trans-4-[2-ethenyl-(4-pyridyl)]-aniline (D43)

A suspension of trans-4-[2-ethenyl-(4-pyridyl)]-nitrobenzene (D42) (0.5g, 2.2 mmol) in ethanol (30 ml) at 50° C. was treated with a solution ofstannous (II) chloride (1.25 g, 6.6 mmol) in concentrated hydrochloricacid (2 ml). The mixture was maintained at 50° C. overnight thenevaporated to dryness. The residue was partitioned between ethyl acetateand 5M aqueous sodium hydroxide solution. Drying and evaporationafforded a yellow solid which was triturated with ether-petroleum ether(1:1) affording the title compound as a yellow solid (100 mg, 23%).

¹H NMR (D6-DMSO) 5.50 (2H, bs), 6.60 (2H, d), 6.85 (1H, d), 7.30-7.50(5H, m), 8.45 (2H, d)

Description 44 4-Nitro-2-(pyridin-3-yloxy)pyridine-N-oxide (D44)

Sodium hydride (0.27 g of an 80% dispersion in oil, 9 mmol) was added toa solution of 3-hydroxypyridine (0.854 g, 9 mmol) in ThF (3 ml) at 0° C.The mixture was then stirred for 1 h at room temperature before2-chloro-4-nitropyridine-N-oxide* (2 g, 9 mmol) was added. The resultingsolution was heated at reflux for 16 h, cooled, poured into water (100ml) and extracted with dichloromethane (3×100 ml). The combined extractswere dried (Na₂SO₄) and evaporated. The residue was chromatographed onsilica using ethyl acetate as eluant to afford the title compound (1.74g, 83%) as a solid.

*G. C. Finger and L. D. Starr, J. Am. Chem. Soc., 81, 2674 (1959)

¹H NMR (250 MHz; CDCl₃) δ: 7.42 (2H, m), 7.83 (1H, m), 8.00 (1H, dd, J=8Hz), 2Hz), 8.42 (1H, d, J 8 Hz), 8.51 (1H, m), 8.59 (1H, m).

Description 45 4-Amino-2-(pyridin-3-yloxy)pyridine (D45)

4-Nitro-2-(pyridin-3-yloxy)pyridine-N-oxide (D44) (1 g, 4.3 mmol) inacetic acid (75 ml) was treated with iron powder (1.2 g, 21.4 mmol) atroom temperature. After 2 h the mixture was concentrated under reducedpressure and partitioned between 2M aq NaOH (100 ml) and dichloromethane(4×100 ml). The combined extracts were dried and evaporated to a whitecrystalline solid (0.75 g, 93%) which was used without furtherpurification.

¹H NMR (250 MHz; CDCl₃) δ: 4.25 (2H, br), 6.17 (1H, d, J 2 Hz), 6.33(1H, dd, J 7 Hz, 2 Hz), 7.26 (1H, s), 7.32 (1H, dd, J 8 Hz, 5 Hz), 7.48(1H, m, J 8 Hz), 7.82 (1H, d, J 7 Hz), 8.42 (1H, m, J 5 Hz), 8.48 (1H,d, J 2 Hz).

Description 46 5-Nitro-1-(3-pyridylmethyl)indole (D46)

5-Nitroindole (0.49, 3 mmol) was treated with sodium hydride (0.198 g,6.6 mmol) in dry dimethylformamide (20 ml). After 15 min at roomtemperature, 3-picolyl chloride hydrochloride (0.49 g, 3 mmol) was addedand the mixture was stirred at room temperature for 24 h, then pouredinto water. The precipitate was filtered off, washed with water anddried to give the title compound (0.67 g, 88%), m.p. 131-4° C.

¹H NMR (CDCl₃) δ: 5.40 (2H, s), 6.75 (1H, d, J=3), 7.2-7.4 (4H, m), 8.09(1H, dd, J=8,2), 8.52 (1H, s), 8.57 (1H, d, J=4), 8.61 (1H, d, J=2).

MS(API) m/z=254(MH⁺)

Description 47 5-Nitro-1-(4-pyridylmethyl)indole (D47)

The title compound was prepared by the method of Description 46 using4-picolyl chloride hydrochloride. Yield 87%, m.p. 134-136° C.

¹H NMR (CDCl₃) δ: 5.41 (2H, s), 6.80 (1H, d, J=3), 6.93 (2H, d, J=7),7.23 (1H, d, J=8), 7.30 (1H, d, J=3), 8.10 (1H, dd, J=8,2), 8.57 (2H, d,J=7), 8.64 (1H, d, J=2) MS(API) m/z=254(MH⁺)

Description 48 5-Amino-1-(3-pyridylmethyl)indole (D48)

To a stirred suspension of nitroindole (D46) (0.63 g, 2.5 mmol), andiron powder (0.41 g, 7.2 mmol) in methanol (20 ml) was added a solutionof ammonium chloride (0.66 g, 12.4 mmol) in water (13 ml). The mixturewas then heated under reflux for 12 h, then filtered while hot andevaporated. The residue was diluted with water and extracted withdichloromethane. The organic extract was washed with brine, dried andevaporated to give the title compound (0.40 g, 72%) as a gum.

¹H NMR (CDCl₃) δ: 5.25 (2H, s), 6.38 (1H, d, J=3), 6.63 (1H, dd, J=8,2),6.94 (1H, d, J=2), 7.03 (1H, d, J=8), 7.05 (1H, d, J=3), 7.18 (1H, dd,J=7,4), 7.29 (1H, d, J=7), 8.52 (2H, broad s).

MS(API) m/z=224(MH⁺)

Description 49 5-Amino-1-(4-pyridylmethyl)indole (D49)

The title compound was prepared by the method of Description 48, fromnitroindole D47. Yield 87%.

¹H NMR (CDCl₃) δ: 3.52 (2H, broad), 5.27 (2H, s), 6.41 (1H, d, J=3),6.63 (1H, dd, J=8,2), 6.90-7.0 (4H, m), 7.05 (1H, d, J=3), 8.50 (2H, d,J=7).

MS(API) m/z=224(MH⁺)

Description 50 5-Nitro-1-(3-pyridyl)indole (D50)

A mixture of 5-nitroindole (0.49 g, 3 mmol), 3-bromopyridine (0.95 g, 6mmol), copper (I) bromide (60 mg, 0.42 mmol) and potassium carbonate(0.62 g, 4.5 mmol) in pyridine (2 (mL) and nitrobenzene (0.6 mL) washeated under reflux for 4 h. After cooling, the mixture was diluted withwater and extracted wtih ethyl acetate. The organic extract was washedwith water, dried and evaporated. The residue was chromatographed onsilica gel eluted with ethyl acetate to give the title compound (0.62 g,86.5%), mp. 164-5° C.

¹H NMR (CDCl₃) δ: 6.93 (1H, d, J=3), 7.49 (1H, d, J=3), 7.51 (1H, d,J=8), 7.57 (1H, dd, J=7,5), 7.87 (1H, dm, J=7), 8.18 (1H, dd, J=8,2),8.72 (1H, d, J=5), 8.85 (1H, d, J=2)

MS(API) m/z=240(MH⁺)

Description 51 5-Nitro-1-(4-pyridyl)indole (D51)

The title compound was prepared by the method of Description 50, using4-bromopyridine. Yield 0.42 g (59%)

¹H NMR (CDCl₃) δ: 7.09 (1H, d, J=3), 7.79 (2H, d, J=6), 7.94 (1H, d,J=8), 8.09 (1H, d, J=3), 8.13 (1H, dd, J=8,2), 8.69 (1H, d, J=2), 8.80(2H, broad)

MS(API) m/z=240(MH⁺)

Description 52 5-Amino-1-(3-pyridyl)indole (D52)

The title compound was prepared by the method of Description 48, fromnitroindole (D50). Crude product was chromatographed on silica geleluted with ethyl acetate to give the title compound (0.34 g, 63%) as agum.

¹H NMR (CDCl₃) δ: 3.59 (2H, broad), 6.55 (1H, d, J=3), 6.71 (1H, dd,J=8,2), 6.98 (1H, d, J=2), 7.25 (1H, d, J=3), 7.37 (1H, d, J=8), 7.64(1H, dd, J=7,5), 7.82 (1H, dm, J=7), 8.58 (1H, d, J=5), 8.81 (1H, d,J=2)

MS(API) m/z=210(MH⁺)

Description 53 5-Amino-1-(4-pyridyl)indole (D53)

A mixture of nitroindole (D51, 0.41 g, 1.8 mmol), tin (II) chloride (1.7g, 8.8 mmol), and concentrated hydrochloric acid (2 ml) in ethanol (10ml) was heated under reflux for 70 min. The mixture was evaporated andthe residue was dissolved in water, basified with dilute sodiumhydroxide and extracted with dichloromethane. The extract was dried andevaporated to give the title compound (0.36 g, 96%).

¹H NMR (CDCl₃) δ: 3.62 (2H, broad), 6.56 (1H, d, J=3), 6.72 (1H, dd,J=8,2), 6.95 (1H, d, J=2), 7.32 (1H, d, J=3), 7.41 (2H, d, J=6), 7.54(1H, d, J=8), 8.68 (2H, d, J=6)

MS(API) m/z=210(MH⁺)

DESCRIPTION 54 5-Methylthio-6-trifluoromethyl-1-(3-ethoxycarbonylphenylcarbamoyl)-indoline (D54)

This was prepared in 74% yield by urea formation between ethyl3-aminobenzoate and 5-methylthio-6-trifluoromethyl indoline, (D7) usingcarbonyl diimidazole as the coupling agent.

DESCRIPTION 555-Methythio-6-trifluoromethyl-1-(3-carboxyphenylcarbamoyl)-indoline(D55)

This was prepared in 86% by basic hydrolysis of the corresponding esterD54.

¹H NMR (CDCl₃) δ:2.50 (3 H, s), 3.30 (2 H, t), 4.20 (2 H, t), 7.40-7.50(2 H, m), 7.60 (1 H, m), 7.85 (1 H, d), 8.25 (2 H, m), 8.80 (1 H, s)

DESCRIPTION 56 4-(3-Nitrophenyl)-2-(3-pyridyl)-thiazole, hydrobromidesalt

A mixture of 2-bromo-3′-nitroacetophenone (5 g, 20 mmol) andthionicotinamide (2.76 g, 20 mmol) in ethanol (25 ml) was heated toreflux for 1 h, during which time extensive precipitation occurred.Filtration and drying afforded the product as a yellow solid (6.7 g,92%).

¹H NMR δ (DMSO) 7.80 (1 H, t), 7.95 (1 H, m), 8.25 (1 H, dd), 8.55 (1 H,d), 8.70 (1 H, s), 8.90 (3 H, m), 9.45 (1 H, d)

DESCRIPTION 57 4-(3-Aminophenyl)-2-(3-pyridyl)-thiazole

A suspension of 4-(3-nitrophenyl)-2-(3-pyridyl)-thiazole hydrobromide(3.6 g, 10 mmol) in ethanol (150 ml) was treated with a solution of tin(II) chloride (3.7 g, 30 mmol) in concentrated hydrochloric acid (12ml). The mixture was heated at 50° C. for 16 h. A further portion of tin(II) chloride (2.9 g, 15 mmol) was added and the mixture heated at 50°C. for a further 4 hours before being evaporated to dryness. The residuewas partitioned between ethyl acetate and 1M aqueous sodium hydroxide.The ethyl acetate extract was dried (Na₂SO₄) and filtered through a plugof silica. Evaporation afforded the title compound as a yellow solid(2.15 g, 85%).

¹H NMR (CDCl₃) δ:3.80 (2 H, bs), 6.70 (1 H, dd), 7.20 (2 H, m), 7.40 (2H, m), 7.50 (1 H, s), 8.30 (1 H, dt), 8.65 (1 H, dd), 9.25 (1 H, d).

DESCRIPTION 58 4-(4-Nitrophenyl)-2-(4-pyridyl)-thiazole

This was prepared in the same manner as4-(3-nitrophenyl)-2-(3-pyridyl)-thiazole, hydrobromide salt andliberated to the free base form with 5M NaOH to give the product as abrown solid (4 g, 69%).

¹H NMR (CDCl₃) δ:8.8 (2 H, d), 8.35 (2 H, d), 8.15 (2 H, d), 7.9 (2 H,d), 7.8 (1 H, s).

DESCRIPTION 59 4-Fluoro-3-(pyrid-3-yl)phenylcarbonyl azide (D59)

3-Bromo-4-fluorobenzotrifluoride was coupled with 3-pyridylboronic acidusing Suzuki methodology. Hydrolysis of the product using conc.sulphuric acid and chlorosulphonic acid followed by esterification inmethanol and conc. sulphuric acid gave methyl4-fluoro-3-(Pyrid-3-yl)benzoate. Treatment with hydrazine hydrateafforded the hydrazide which was diazotised with sodium nitrite andbasified with potassium carbonate to give the title compound.

¹H NMR 250 MHz δ:8.82 (br, 1 H), 8.67 (br, 1 H), 8.17 (dd, 1 H), 8.09(m, 1 H), 7.90 (dd, 1 H), 7.42 (m, 1 H), 7.30 (m, 1 H).

DESCRIPTION 60 3-Fluoro-5-(pyrimidin-5-yl)phenylcarbonyl azide (D60)

3-Bromo-5-fluorobenzotrifluoride was lithiated with n-butyllithium andtreated with tri-isopropylborate to give3-fluoro-5-trifluoromethylphenyl boronic acid. This was coupled to5-bromopyrimidine, using Suzuki methodology to afford3-fluoro-5-(pyrimidin-5-yl)benzotrifluoride. Hydrolysis with conc.sulphuric acid and chlorosulphonic acid afforded3-fluoro-5-(pyrimidin-5-yl)benzoic acid. This was converted to themethyl ester by treatment with methanol and conc. sulphuric acid, and tothe hydrazide by treatment with hydrazine hydrate. Diazotisation andtreatment with potassium carbonate afforded the title compound.

¹H NMR (200 MHz, CDCl₃) δ (ppm):7.57 (1 H, dt J=1, 8), 7.83 (1 H, m),8.06 (1 H, t, J=1), 8.99 (2 H, s), 9.29 (1 H, s)

DESCRIPTION 61 4-Chloro-3-(4-methyl-3-pyridyl)nitrobenzene (D61)

The title compound was prepared by a Suzuki coupling of3-bromo-4-chloronitrobenzene and 4-methyl-3-pyridylboronic acid. Thisgave (D61) (0.2 g, 33%).

DESCRIPTION 62 4-Chloro-3-(4-methyl-3-pyridyl)aniline (D62)

The title compound was prepared by stannous chloride reduction of thenitro compound (D61). This gave (D62) (0.105 g, 95%).

DESCRIPTION 63 2,3-Dihydro-5-nitro-7-(pyrid-3-yl)benzofuran (D63)

2,3-Dihydro-7-iodo-5-nitrobenzofuran (0.76 g, 0.0026 mole) and3-pyridylboronic acid (0.32 g, 0.0026 mole) in 50% aqueous1,2-dimethoxyethane (50 ml) were treated under argon with sodiumcarbonate (1.17 g, 0.011 mole) and tetrakis triphenylphosphine palladium(0) (0.06 g, 0.06 g, 0.000052 mole) and heated under reflux for 18hours. The mixture was allowed to cool to ambient temperature, dilutedwith deionised water, extracted into ethyl acetate, dried (Na₂SO₄) andevaporated in vacuo. The residue was purified by flash columnchromatography on silica gel, eluting with 30% ethyl acetate/60-80°petroleum ether to afford the title compound (0.19 g, 30%) as a yellowsolid.

¹H NMR (200 MHz, CDCl₃) δ (ppm):3.40 (2 H, t, J=9), 4.83 (2 H, t, J=9),7.40 (1 H, q, J=3,5), 8.02 (1 H, dt, J=1,9), 8.12 (1 H, m), 8.30 (1 H,d, J=3), 8.62 (1 H, dd, J=1,5), 8.98 (1 H, d, J=1).

DESCRIPTION 64 5-Amino-2,3-dihydro-7-(pyrid-3-yl)benzofuran (D64)

2,3-Dihydro-5-nitro-7-(pyrid-3-yl)benzofuran (D63) (0.19 g, 0.00079mole) in ethanol (20 ml) was treated with a solution of tin II chloride(0.75 g, 0.0040 mole) in conc. hydrochloric acid (1 ml) and heated at50° C for 2 hours. A further 0.38 g tin II chloride in conc.hydrochloric acid (0.5 ml) was added and the mixture was heated at 50°C. for ½ hour and stirred at ambient temperature for 18 hours. Deionisedwater (5 ml) was added and the mixture was basified with 10% sodiumhydroxide solution, extracted into ethyl acetate, dried (Na₂SO₄) andevaporated in vacuo to afford the title compound (0.13 g, 82%) as a darkoil.

¹H NMR (200 MHz, CDCl₃) δ (ppm):3.20 (2 H, t, J=9), 3.43-3.70 (2 H, brs), 4.57 (2 H, t, J=9), 6.63 (2 H, s),7.32 (1 H, dt, J=1,5), 8.51 (1 H,dd, J=1,5), 8.89 (1 H, t, J=1).

DESCRIPTION 65 PhenylN-[2,3-dihydro-7-(pyrid-3-yl)benzofuran-5-yl]carbamate (D65)

5-Amino-2,3-dihydro-7-(pyrid-3-yl)benzofuran (D64) (0.13 g, 0.00062mole) was dissolved in dichloromethane (10 ml) and cooled to 0° C. underargon. Triethylamine (0.09 ml, 0.00068 mole) was added, followeddropwise by phenyl chloroformate (0.08 ml, 0.00065 mole) and the mixturewas stirred at ambient temperature for 2 hours. The reaction mixture waswashed with deionised water, dried (Na₂SO₄) and evaporated in vacuo toafford the title compound (0.20 g, 97%) as a cream solid.

¹H NMR (200 MHz, CDCl₃) δ (ppm):3.38 (2 H, t, J=9), 4.64 (2 H, t, J=9),7.05-7.58 (9 H, m), 8.06 (1 H, dt, J=1, 5), 8.57 (1 H, dd, J=1,5), 8.95(1 H, d, J=1).

DESCRIPTION 66 Phenyl N-(3-Fluoro-5-(pyrid-3-yl)phenyl)carbamate (D66)

3-Fluoro-5-(pyrid-3-yl)aniline (1.05 g, 0.0050 mole) in drydichloromethane was treated under argon with triethylamine (1.12 ml,0.0080 mole) followed dropwise by phenyl chloroformate (0.97 ml, 0.0077mole) and stirred at ambient temperature for 18 hours. The reactionmixture was washed (x2) with deionised water, dried (Na₂SO₄) andevaporated in vacuo to afford the title compound (1.1 g, 71%) as an offwhite solid.

¹H NMR (200 MHz; D⁶DMSO) δ:7.20-7.49 (3 H, m), 7.49-7.59 (5 H, m), 7.63(1 H, d), 8.07 (1 H, dt), 8.63 (1 H, d), 8.87 (1 H, s), 10.61 (1 H, s)

DESCRIPTION 67 Phenyl N-(4-Chloro-3-(pyrid-3-yl)phenyl)carbamate (D67)

4-Chloro-3-(pyrid-3-yl)aniline (0.08 g, 0.00039 mole) in isopropylalcohol (8 ml) was cooled to −40° C. and treated under argon withtriethylamine (0.06 ml, 0.00043 mole) followed dropwise by phenylchloroformate (0051 ml, 0.00041 mole). The reaction mixture was stirredat −40° C. for half an hour and allowed to warm to ambient temperature.The solvent was removed in vacuo and the residue dissolved indichloromethane, washed with H₂O, dried (Na₂SO₄) and evaporated in vacuoto afford the title compound (0.12 g, 95%) as an orange solid.

¹H NMR (200 MHz; CDCl₃) δ;7.05-7.56 (10 H, m), 7.82 (1 H, dt), 8.64 (1H, dd), 8.71 (1 H, d)

DESCRIPTION 68 Phenyl N-[(5-Methyl-1,2,4-oxadiazol-3-yl)phenyl]carbamate(D68)

The title compound (0.23 g, 97%) was prepared using the method of D67.

¹H NMR (200 MHz, CDCl₃) δ:2.65 (3 H, s), 7.08 (1 H, s), 7.16-7.53 (6 H,m), 7.66-7.87 (2 H, m), 8.06 (1 H,t).

DESCRIPTION 69 Phenyl N-[4-Methyl-3-(4-methylpyrid-3-yl)phenyl]carbamate(D69)

The title compound was prepared as in the method of description 67 fromthe corresponding aniline. This gave (2.1 g, 97%) of an oil.

¹H NMR (CDCl₃) δ:2.05 (3 H, s), 2.15 (3 H, s), 7.08-7.45 (10 H, m), 8.30(1 H, s), 8.48 (1 H, d, J=8 Hz).

EXAMPLE 1 1-[(3-Pyridyl)-3-phenyl carbamoyl]-5-methoxy-6-trifluoromethylindoline

3-(3-Pyridyl)aniline (0.27 g, 1.6 mmol) in dichloromethane (5 ml) wasadded dropwise over 5 minutes to a solution of 1,1-carbonyldimidazole(0.28 g, 1.75 mmol) in dichloromethane (5 ml). After 2 hour the mixturewas evaporated to dryness and the residue dissolved inN,N-dimethylformamide (20 ml). 5-Methoxy-6-trifluoromethyl indoline(0.35 g, 1.6 mmol) was added and the mixture was set aside in the fridgefor 1 h. Filtration and drying afforded a brown solid (0.59 g).Chromatography on silica, eluting with a gradient of 0-3% methanol indichloromethane afforded the title compound as a white solid (0.56 g,85%), mp 193-4° C.

¹H NMR (D⁶DMSO) 3.25 (2 H, t), 3.85 (3 H, s), 4.20 (2 H, t) 7.20 (1 H,s), 7.40 (2 H, m), 7.50 (1 H, m), 7.90 (1 H, dm), 8.15 (1 H, s), 8.60 (1H, dm), 8.70 (1 H, s), 8.85 (1 H, s).

The mesylate salt can be prepared by treatment with methanesulphonicacid in acetone.

The following examples were similarly prepared:

EXAMPLE 2 1-[(4-Pyridyl)-3-phenylcarbamoyl]-5-methylthio-6-trifluoromethyl indoline

Yield=25%

¹H NMR (D⁶-DMSO) 2.52 (3 H, s), 3.30 (2 H, t), 4.25 (2 H, t), 7.50 (3 H,m), 7.70 (3 H, m), 8.02 (1 H, s), 8.70 (2 H, dd), 8.80 (1 H, s).

EXAMPLE 3 1-[(3-Pyridyl)-3-phenylcarbamoyl]-5-methylthio-6-trifluoromethyl indoline

Yield=42%, m.p. 208-210° C.

¹H MNR (D⁶DMSO) 2.50 (3 H, s), 3.30 (2 H, t), 4.20 (2 H, t), 7.40 (3 H,m), 7.50 (1 H, M), 7.65 (1 H, m), 7.90 (1 H, s), 8.10 (1 H, dm), 8.20 (1H, s), 8.60 (1 H, m), 8.80 (1 H, s), 8.90 (1 H, m).

The mesylate salt can be prepared by treatment with methanesulphonicacid in acetone.

EXAMPLE 4 1-[(3-Pyridyl)-4-phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline

Yield=85%, m.p.=>230° C.

¹H NMR (D⁶-DMSO) 3.30 (2 H, t), 3.85 (3 H, s), 4.20 (2 H, t), 7.20 (1 H,s), 7.45 (1 H, m), 7.70 (4 H, m), 8.05 (1 H, m), 8.15 (1 H, s), 8.55 (1H, m), 8.70 (1 H, s), 8.90 (1 H, m)

EXAMPLE 5 1-[(4-Pyridyl)-4-phenyl carbamoyl]-5-methoxy-6-trifluoromethylindoline

Yield=5%, m.p.=>210° C.

¹H NMR (D⁶-DMSO) 3.30 (2 H, t), 3.85 (3 H, s), 4.20 (2 H, t), 7.20 (1 H,s), 7.70 (2 H, d), 7.75 (4 H, m), 8.15 (1 H, s), 8.60 (2 H, d), 8.85 (1H, s)

EXAMPLE 6 1-[(2-Pyridyl)-3-phenyl carbamoyl]-5-methoxy-6-trifluoromethylindoline

Yield=40%, m.p.=220-225° C. ¹H NMR (D⁶-DMSO) 3.30 (2 H, t), 3.85 (3 H,s), 4.20 (2 H, t), 7.20 (1 H, s), 7.40 (2 H, m), 7.70 (2 H, m), 7.90 (2H, m), 8.15 (1 H, s), 8.65 (1 H, m), 8.70 (1 H, s).

EXAMPLE 71-[4-Methyl-3-(3-Pyridyl)-phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline

Yield=26%, m.p.=211-212° C.

¹H NMR (D⁶-DMSO) 2.2 (3 H, s), 3.28 (2 H, t), 3.85 (3 H, s), 4.11 (2 H,t), 6.44 (1 H, s), 6.85 (1 H, s), 7.18-7.45 (4 H, m), 7.59-7.72 (1 H,m), 8.22 (1 H, s), 8.49-8.69 (2 H, m).

The mesylate salt can be prepared by treatment with methanesulphonicacid in acetone.

EXAMPLE 81-[3-Fluoro-5-(3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline

Yield=26%, m.p.=220-223° C.

¹H NMR (D⁶-DMSO) 3.29 (2 H, t), 3.85 (3 H, s), 4.21 (2 H, t), 7.23 (1 H,s), 7.30 (1 H, t), 7.54 2 H, m), 7.65 (1 H, dt), 7.76 (1 H, s), 8.09 (1H, dt), 8.15 (1 H, s), 8.62 (1 H, dd), 8.78-9.00 (2 H, m).

The mesylate salt can be prepared by treatment with methanesulphonicacid in acetone. m.p. 198-199° C.

EXAMPLE 9 1-[2-Fluoro-5-(3-pyridyl) phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline

Yield=10%, m.p. 233° C. (decomp)

¹H NMR (D⁶-DMSO) 3.20 (2 H, t), 3.82 (3 H, s), 3.94 (2 H, t), 7.13-7.28(2 H, m), 7.38-7.58 (3 H, m), 7.87 (1 H, dt), 7.98 (1 H, S), 8.35 (1 H,s), 8.55 (1 H, dd), 8.64 (1 H, d)

EXAMPLE 10 1-(5-Phenyl pyrid-3-yl carbamoyl)-5-methoxy-6-trifluoromethylindoline

A mixture of 1-(5-bromo-pyrid-3-ylcarbamoyl)-5-methoxy-6-trifluoromethyl-indoline (D14, 208 mg, 0.5 mmol),phenyl boronic acid (300 mg, 2.4 mmol), sodium carbonate (0.32 g, 3mmol) and tetrakis (triphenylphosphine) palladium (0) (30 mg) indimethoxyethane-water (5 ml-1 ml) was heated to reflux under argon for10 h. The cooled reaction mixture was partitioned between ethylacetate-half saturated brine. The organic extract was dried andevaporated affording a brown solid (0.14 g). Chromotography on silica,eluting with a gradient of 0-5% methanol in ethyl acetate afforded thetitle compound as a white crystalline solid (100 mg, 48%), m.p. 162-164°C.

¹H NMR (D⁶-DMSO) 3.30 (2 H, t) 3.85 (3 H, s), 4.20 (3 H, t), 7.20 (1 H,s), 7.50 (3 H, m), 7.70 (2 H, m), 8.10 1 H, s), 8.30 (1 H, m), 8.55 (1H, m), 8.75 (1 H, m), 8.75 (1 H, m), 8.85 (1 H, s).

The mesylate salt can be prepared by treatment with methanesulphonicacid in acetone.

The following examples were similarly prepared.

EXAMPLE 11 1-(5-Phenyl pyrid-3-ylcarbamoyl)-5-methylthio-6-trifluoromethyl indoline

Yield=73%, m.p.=208-214° C.

¹H NMR (D⁶-DMSO) 2.50 (2 H, s), 3.30 (2 H, t), 4.20 (2 H, t), 7.50 (4 H,m), 7.70 (2 H, m), 8.20 (1 H, s), 8.30 (1 H, m), 8.60 (1 H, m), 8.75 (1H, m), 8.95 (1 H, s).

EXAMPLE 12 1-[5-(3-Pyridyl)-pyrid-3-ylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline

Yield=29%, m.p.=113-114° C.

¹H NMR (D⁶-DMSO) 3.30 (2 H, t), 3.85 (3 H, s), 4.20 (2 H, t), 7.20 (1 H,s), 7.55 (1 H, m), 8.10 (1 H, m), 8.15 (1 H, s), 8.30 (1 H, m), 8.60 (1H, ), 8.65 (1 H, dd), 8.80 (1 H, d), 8.95 (2 H, m)

The mesylate salt can be prepared by treatment with methanesulphonicacid in acetone.

EXAMPLE 13 1-[5-(4-Trifluoromethylphenyl)-pyrid-3-ylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline

Yield=48%, m.p.=199-202° C.

¹H NMR (D⁶-DMSO) 3.30 (2 H, t), 3.85 (3 H, s), 4.20 (2 H, t), 7.20 (1 H,s), 7.89 (4 H, m), 8.10 (1 H, s), 8.35 (1 H, m), 8.60 (1 H, d), 8.80 (1H, d), 8.95 (1 H, s).

EXAMPLE 14 1-[5-(4-Methylphenyl)-pyrid-3ylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline

Yield=57%, m.p.=190-191° C.

¹H NMR (D⁶-DMSO) 2.35 (3 H, s), 3.30 (2 H, t), 3.85 (3 H s), 4.20 (2 H,t), 7.20 (1 H, s, 7.30 (2 H, d), 7.60 (2 H, d), 8.15 (1 H, m), 8.55 (1H, d), 8.75 (1 H, d), 8.85 (1 H, s).

EXAMPLE 15 1-[5-(2-Thienyl)-pyrid-3-ylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline

Yield=53%, m.p.=193-208° C.

¹H NMR (D⁶-DMSO) 3.30 (2 H, t), 3.85 (3 H, s), 4.20 (2 H, t), 7.20 (2 H,m), 7.65 (2 H, m), 8.10 (1 H, s), 8.25 (1 H, t), 8.60 (1 H, d), 8.75 (1H, d), 8.85 (1 H, s).

The mesylate salt can be prepared by treatment with methanesulphonicacid in acetone.

EXAMPLE 16 1-[5-(3-Thienyl)-pyrid-3-ylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline

Yield=30%, m.p.=165-167° C.

¹H NMR (D⁶-DMSO) 3.30 (2 H, t), 3.85 (3 H, s), 4.20 (2 H, t), 7.20 (1 H,s), 7.60 (1 H, dd), 7.75 (1 H, m), 8.0 (1 H, s, 8.30 (1 H, t), 8.65 (1H, d), 8.70 (1 H, d), 8.90 (1 H, s

EXAMPLE 17 1-[5-(2-Pyrrolyl)-pyrid-3-ylcarbamoyl)-5-methoxy-6-trifluoromethyl indoline

Yield=20%, m.p.=218-219° C.

¹H NMR (D⁶-DMSO) 3.30 (2H, t), 3.85 (3H, s), 4.20 (2H, t), 6.20 (1H, m),6.55 (1H, m), 6.90 (1H, m), 7.20 (1H, s), 8.15 (2H, m), 8.50 (1H, d),8.60 (1H, d), 8.80 (1H, s).

EXAMPLE 18 1-[5-(4-Pyridyl)-pyrid-3-ylcarbamoyl]-5-methoxy-6-trifluoromethylindoline

Yield=71%, m.pt 230-234° C.

¹H NMR (D⁶-DMSO) 3.30 (2H, t), 3.85 (3H, s), 4.20 (2H, t), 7.20 (1H, s),7.75 (2H, m) 8.15 (1H, s), 8.40 (1H, t), 8.65 (1H, d), 8.70 (2H, m),8.85 (1H, d).

EXAMPLE 19 1-[2-(3-Pyridyl)-thiazol-4-ylcarbamoyl]-5-methoxy-6-trifluoromethylindoline

A solution of acyl azide (D15) (370 mg, 1.6 mmol) in toluene (5 ml) washeated to reflux for 0.25 h. After cooling to room temperature, thesolution of the isocyanate was added to a solution of5-methoxy-6-trifluoromethyl indoline (0.35 g, 1.6 mmol) indichloromethane (10 ml). Filtration and drying afforded the titlecompound as a white solid (100 mg, 15%), m.p.>200° C.

¹H NMR 3.30 (2H, t), 3.85 (3H, s), 4.20 (2H, t), 7.20 (1H, s), 7.45 (1H,m), 7.55 (1H, s), 8.15 (1H, s), 8.30 (1H, dt), 8.65 (1H, dd), 9.15 (1H,m), 9.85 (1H, s).

EXAMPLE 20 1-[2-(2-Pyridyl)-thien-5-ylcarbamoyl]-5-methoxy-6-trifluoromethylindoline

This was prepared from the corresponding acyl azide (D16) using the sameprocedure as for Example 19, affording the title compound as a paleyellow solid (0.45 g, 73%), m.p. 205-215° C.

¹H NMR (D⁶-DMSO) 3.30 (2H, t), 3.85 (3H, s), 4.20 (2H, t), 6.80 (1H,d),7.15 (1H, m), 7.25 (1H, s), 7.50 (1H, d), 7.75 (2H, m), 8.20 (1H, S),8.45 (1H, m), 9.95 (1H, s).

EXAMPLE 211-(3-Fluoro-5-(4-methyl-3-pyridyl)phenylcarbamoyl)-5-methoxy-6-trifluoromethylindoline

A mixture of1-(3-fluoro-5-iodophenylcarbamoyl)-5-methoxy-6-trifluoromethylindoline(D17, 0.31 g, 0.65 mmol), 4-methyl-3-pyridylboronic acid (88 mg, 0.65mmol), tetrakis (triphenylphosphine) palladium (O) (23 mg, 0.02 mmol)and sodium carbonate (0.31 g, 3.0 mmol) in 1,2-dimethoxyethane (20 mL)and water (2 mL) was heated under reflux for 24 h, then cooled andpoured into water. The aqueous mixture was extracted withdichloromethane/methanol, and the organic extract was ashed with brine,dried and evaporated. The residue was chromatographed on silica geleluted with 2-3% methanol/dichloromethane to give the title compound,which was recrystallised from dichloromethane/petrol (80 mg, 28%), Mp191-5° C.

¹H NMR (d₆DMSO) δ: 2.31 (3H, s), 3.28 (2H, t, J=8), 3.85 (3H, s), 4.19(2H, t, J=8), 6.94 (1H, d, J=8), 7.22 (1H, s), 7.37 (1H, d, J=6), 7.42(1H, s), 7.61 (1H, d, J=12(, 8.12 (1H, s), 8.40 (1H, s), 8.46 (1H,d,J=6), 8.82 (1H, s).

MS (API): Found m/z=446 (MH⁺), C₂₃H₁₉N₃O₂F₄ requires M+1=446.

EXAMPLE 221-(5-(2,6-Difluorophenyl)-3-pyridylcarbamoyl)-5-methoxy-6-trifluoromethylindoline

A solution of 5-(2,6-difluorophenyl)nicotinoyl azide (D20, 0.46 g, 1.8mmol) in toluene (10 mL) was heated under reflux for 2 h. After cooling,a solution of 5-methoxy-6-trifluoromethylindoline (D11, 0.40 g, 1.8mmol) in dichloromethane (10 mL) was added and the mixture was stirredovernight at room temperature. The precipitate was filtered off andwashed with petrol. The crude product was recrystallised fromdichloromethane/petrol to give the title compound (0.66 g, 82%), Mp.217-9° C.

¹H NMR (d₆DMSO) δ: 3.29 (2H, t, J=8), 3.84 (3H, s),4.21 (2H, t, J=8),7.22 (1H, s), 7.29 (2H, t, J=7), 7.56 (1H, quintet, J=7), 8.11 (1H, s),8.15 (1H, s), 8.32 (1H, s), 8.80 (1H, s), 9.93 (1H, s).

MS (API): m/z=450 (MH⁺), C₂₂H₁₆N₃O₂F₅ requires M+1=450.

Found: C, 54.84; H, 3.69; N, 8.65% C₂₂H₁₆N₃O₂F₅ requires C, 58.80: H,3.59; N, 9.35%.

EXAMPLE 236-Chloro-5-methyl-1-(4-methyl-3-(pyrid-3-yl)-phenylcarbamoyl)indoline

4-Methyl-3-(pyrid-3-yl) aniline (0.30 g, 0.0016 mole) in drydichloromethane (20 ml) was added, under argon, to1,1′-carbonyldiimidazole in dry dichloromethane (10 ml) (0.30 g, 0.0018mole) and stirred at ambient temperature for 1 hour. The solvent wasremoved in vacuo and the residue dissolved in dry dimethylformamide (30ml). 6-Chloro-5-methylindoline (see WO 95/01976) (0.27 g, 0.0016 mole)in dry dimethylformamide (10 ml) was added and the mixture heated to100° C. for 1 hour. After cooling to ambient temperature, the solventwas removed in vacuo and the residue diluted with deionised water (15ml), extracted into dichloromethane (2×20 ml), dried (Na₂SO₄) andevaporated in vacuo. The residue was purified by flash columnchromatography on silica gel, eluting with 3% methanol/dichloromethaneand the resulting solid recrystallised from ethylacetate/methanol/60-80° petroleum ether to afford the title compound(0.31 g, 57%) as a cream solid (mp 202-203° C.).

¹H NMR (270 MHz, d⁶DMSO) δ: 2.20 (3H, s), 2.24 (3H, s), 3.12 (2H, t,J=7), 4.13 (2H, t, J=7), 7.14 (1H, s), 7.25 (1H,d, J=7), 7.42-7.61 (3H,m), 7.81 (1H, dt, J=3, 7), 7.89 (1H, s), 8.49-8.69 (3H, m).

MS (EI) m/z=377 (M⁺).

The mesylate salt can be prepared by treatment with methanesulphonicacid in acetone.

EXAMPLE 24 1-(4-Methyl-3-(pyrid-3-yl)phenylcarbamoyl)-5-thiomethyl-6-trifluoromethylindoline

4-Methyl-3-(pyrid-3-yl) aniline (0.35 g, 0.0019 mole) in drydichloromethane (20 ml) was added, under argon, to1,1′-carbonyldiimidazole (0.34 g, 0.0021 mole) in dry dichloromethane(10 ml) and stirred at ambient temperature for 1 hour. The solvent wasremoved in vacuo and the residue dissolved in dry dimethylformamide (10ml). 5-Thiomethyl-6-trifluoromethylindoline (D7) (0.44 g, 0.0019 mole)in dry dimethylformamide (5 ml) was added and the mixture heated to 100°C. for 2 hours. After cooling to ambient temperature, the solvent wasremoved in vacuo and the residue diluted with deionised water (15 ml),extracted into dichloromethane (2×20 ml), dried (Na₂SO₄) and evaporatedin vacuo. The residue purified by flash column chromatography on silicagel eluting with 3% methanol/dichloromethane and the resulting solid wasrecrystallised from ethyl acetate/60-80° petroleum ether to afford thetitle compound (0.11 g, 13%) as a cream solid (mp 221-223° C.).

¹H, NMR (200 MHz; d⁶DMSO) δ: 2.20 (3H, s), 2.55 (3H, s), 3.38 (2H, t,J=8), 4.20 (2H, t, J=8), 7.26 (1H, d, J=9), 7.41-7.61 (4H, m), 7.81 (1H,dt, J=3,9), 8.20 (1H, s), 8.51-8.63 (2H, m), 8.69 (1H, s).

MS (CI) m/z=444 (MH⁺).

EXAMPLE 251-(3-Fluoro-5-(pyrid-3-yl)phenylcarbamoyl)-5-thiomethyl-6-trifluoromethylindolinehydrochloride

Phenyl N-(3-fluoro-5-(pyrid-3-yl)phenyl)carbamate (D66) (0.55 g, 0.0018mole) in dry dimethylformamide (30 ml) was treated, under argon, with5-thiomethyl-6-trifluoromethyl indoline hydrochloride (D7) (0.49 g,0.0018 mole) and triethylamine (0.5 ml, 0.0036 mole) and heated to 100°C. for 6 hours. After cooling to ambient temperature, the solvent wasremoved in vacuo. The residue was purified by flash columnchromatography on silica gel, eluting with 3% methanol/dichloromethaneand the resulting solid recrystallised from ethyl acetate/60-80°petroleum ether to afford the title compound (0.39 g, 49%) as an offwhite solid (mp 202-203° C.).

¹H NMR (250 MHz, d⁶DMSO) δ: 2.52 (3H, s), 3.32 (2H, t, J=8), 4.22 (2H,t, J=8), 7.30 (1H, d, J=8), 7.45-7.58 (3H, m), 7.64 (1H, d, J=11), 7.78(1H, s), 8.09 (1H, d, J=8), 8.23 (1H, s), 8.63 (1H, d, J=6), 8.87-9.01(2H, m).

MS (Electron Spray) m/z=448 (MH⁺).

EXAMPLE 261-(4-Chloro-3-(pyrid-3-yl)phenylcarbamoyl)-5-methoxy-6-trifluoromethylindoline

Phenyl N-(4-Chloro-3-(pyrid-3-yl)carbamate (D67) (0.12 g, 0.00037 mole)in dry dimethylformamide (6 ml) was treated under argon, with5-methoxy-6-trifluoromethylindoline (D11) (0.08 g, 0.0037 mole) andheated to 120° C. for 2 hours. After cooling to ambient temperature, thesolvent was removed in vacuo. The residue was partitioned between 1Naqueous sodium hydroxide solution and dichloromethane. The organic layerwas dried (Na₂SO₄) and evaporated in vacuo. The residue was trituratedin diethyl ether, filtered and dried in vacuo at 60° C. to afford thetitle compound (0.06 g, 36%) as a grey-green solid (mp 210-213° C.).

¹H NMR (200 MHz; CDCl₃) δ: 3.30 (2H, t, J=9), 3.87 (3H, s), 4.12 (2H, t,J=9), 6.56 (1H, s), 6.87 (1H, s), 7.29-7.58 (4H, m), 7.81 (1H, d, J=8),8.21 (1H, s), 8.60 (1H, d, J=5), 8.69 (1H, d, J=3).

MS (EI) m/z=447 (M⁺).

EXAMPLE 275-Methoxy-1-(5-methyl-(1,2,4-oxadiazol-3-yl)-phenylcarbamoyl)-6-trifluoromethylindoline(E27)

Phenyl N-(5-Methyl-(1,2,4-oxadiazol-3-yl)phenyl)carbamate (D68) (0.23 g,0.00078 mole) in dry dimethylformamide (10 ml) was treated, under argon,with 5-methoxy-6-trifluoromethylindoline (0.17 g, 0.00078 mole) (D11)and heated to 120° C. for 4 hours. After cooling to ambient temperature,the solvent was removed in vacuo. The residue was partitioned betweenwater and dichloromethane and the organic layer was dried (Na₂SO₄) andevaporated in vacuo. The residue was purified by flash columnchromatography on silica gel eluting with 5% methanol/dichloromethane.The resulting solid was recrystallised from ethyl acetate/60-80°petroleum ether to leave the title compound (0.11 g, 34%) as a beigesolid (mp 203-204° C.).

¹H NMR (250 MHz; d⁶DMSO) δ: 2.68 (3H, s), 3.30 (2H, t, J=8), 3.85 (3H,s), 4.21 (2H, t, J=8), 7.21 (1H, s), 7.49 (1H, t, J=7), 7.66 (1H, d,J=7), 7.81 (1H, d, J=7), 8.16 (1H, s), 8.33 (1H, s), 8.82 (1H, s).

MS (Electron Spray) m/z=419 (MH⁺).

EXAMPLE 281-[4-Methyl-3-(4-methyl-3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline(E28)

Phenyl N-(4-Methyl-3-(4-methylpyrid-3-yl)phenyl)carbamate (D69) (0.5 g0.0016 mole) in dry dimethylformamide (20 ml) was treated with5-methoxy-6-trifluoromethylindoline (D11) (0.34 g, 0.0016 mole) underargon and heated to 100° C. for 6 hrs. The mixture was allowed to cooland evaporated to dryness in vacuo. The residue was dissolved indichloromethane and the solution washed with 10% aqueous sodiumhydroxide solution (2×20 ml) and then with saturated aqueous sodiumchloride solution (30 ml). The organic phase was then dried (Na₄SO₄)filtered and evaporated to dryness. The residue was purified by flashchromatography on silica gel eluting with 1% methanol/dichloromethane.Trituration of the resulting residue with diethyl ether gave the titlecompound (E28) (0.326 g, 47%) m.p. 138-140° C.

¹H NMR (CDCl₃) δ: 2.00 (3H, s), 2.13 (3H, s), 3.25 (2H, t, J=8 Hz), 3.82(3H, s), 4.12 (2H, t, J=8 Hz), 6.62 (1H, s), 6.81 (1H, s), 7.11-7.29(3H, m), 7.39-7.45 (1H, m), 8.20 (1H, s), 8.30 (1H, s), 8.44 (1H, d, J=6Hz).

M.S. found 442 (MH⁺), C₂₄H₂₂N₃O₂F₃H⁺ requires 442.

EXAMPLE 291-[5-Bromo-3-(pyrid-3-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline(E29)

The title compound was prepared from phenylN-[3-bromo-5-(pyrid-3-yl)phenyl]carbamate (D21) and5-methoxy-6-trifluoromethylindoline (D11) using the method of Example28.

¹H NMR 250 MHz CDCl, δ: 8.74 (1H, s, Ar), 8.54 (dd, 1H, Ar), 8.19 (s,1H, Ar), 7.88 (d, 1H, Ar), 7.74 (s, 1H, Ar), 7.6 (s, 1H, Ar), 7.32-7.44(m, 2H, Ar), 6.82 (br, s, 1H, Ar), 4.15 (t, 2H, indoline), 3.85 (s, 3H,Me), 3.25 (t, 2H, indoline).

EXAMPLE 301-[4-t-Butyl-3-(pyrid-3-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline(E30)

The title compound (0.055 g, 23%) was prepared from phenylN-[4-t-butyl-3-(pyrid-3-yl)phenyl]carbamate (D22) 0.18 g, 0.00052 mole)and 5-methoxy-6-trifluoromethylindoline (D11) using the method ofExample 28.

¹H NMR (200 MHz, CDCl₃) δ: 1.25 (9H, s), 3.27 (2H, t, J=11), 3.85 (3H,s), 4.09 (2H, t, J=11), 6.43 (1H, s), 6.85 (1H, s), 7.00 (1H, d, J=1),7.18-7.35 (1H, m), 7.39-7.69 (3H, m), 8.20 (1H, s), 8.42-8.69 (2H, m).

MS (Electron Spray) m/z=470 (MH⁺).

EXAMPLE 311-[4-Methoxy-3-(pyrid-3-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline(E31)

The title compound (0.21 g, 32%) was prepared from phenylN-[4-methoxy-3-(pyrid-3-yl)phenyl]carbamate (D23) (0.48 g, 0.0015 mole)and 5-methoxy-6-trifluoromethylindoline (D11) using the method ofExample 28.

¹H NMR (200 MHz, D⁶DMSO) δ: 3.26 (2H, t, J=9), 3.76 (3H, s), 3.83 (3H,s), 4.14 (2H, t, J=9), 7.10 (1H, d, J=7), 7.19 (1H, s), 7.45 (1H, dd,J=1,5), 7.54 (1H, s), 7.59 (1H, d, J=3), 7.87 (1H, dt, J=1,5), 8.10 (1H,s), 8.47-8.55 (2H, m), 8.67 (1H, d, J=3).

MS (Electron Spray) m/z=444 (MH⁺).

The mesylate salt can be prepared by treatment with methanesulphonicacid in acetone.

EXAMPLE 321-[5-Fluoro-4-methoxy-3-(pyrid-3-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline(E32)

The title compound (0.34 g, 53%) was prepared from phenylN-[5-fluoro-4-methoxy-3-(pyrid-3-yl)phenyl)carbamate (D24) (0.48 g,0.0014 mole) and 5-methoxy-6-trifluoromethylindoline (D11) using themethod of Example 28.

¹H NMR (200 MHz, D⁶DMSO) δ: 3.38 (2H, t, J÷8), 3.68 (3H, s), 3.84 (3H,s), 4.17 (2H, t, J=8), 7.21 (1H, s), 7.43 (1H, s), 7.51 (1H, dd, J=5.9),7.66 (1H, dd, J=3.20), 7.91 (1H, dt, J=1,8), 8.12 (1H, s), 8.61 (1H, dd,J=3,5), 8.70 (1H, d, J=3), 8.75 (1H, s).

MS (Electron Spray) m/z=462 (MH⁺).

EXAMPLE 331-[3-Bromo-4-methyl-5-(3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline(E33)

A mixture of1-(3,5-dibromo-4-methylphenylcarbamoyl)-5-methoxy-6-trifluoromethylindoline(D25, 0.51 g, 1 mmol), 3-pyridylboronic acid (0.12 g, 1 mmol), tetrakis(triphenylphosphine)palladium (0) (35 mg, 0.03 mmol) and sodiumcarbonate (0.41 g, 4 mmol) in dimethoxyethane (30 mL) and water (3 mL)was heated under reflux, under argon, for 18 h. The mixture was cooledand poured into water. The precipitate was filtered off, washed withwater and dried. The crude product was chromatographed on silica gel,eluted with ethyl acetate, and the eluted material was triturated withether to give the title compound (0.14 g, 28%), m.p. 216-8° C.

NMR (d₆-DMSO) δ: 2.20 (3H, s), 3.25 (2H, t, J=8), 3.84 (3H, s), 4.15(2H, t, J=8), 7.20 (1H, s), 7.50 (1H, s+1H, m), 7.82 (1H, d, J=7), 8.03(1H, s), 8.11 (1H, s), 8.57 (1H, s), 8.62 (1H, d, J=4), 8.71 (1H, s).

MS (API) m/z 506 (MH⁺, ⁷⁹Br), 508 (MH⁺, ⁸¹Br).

EXAMPLE 341-[3-(4-Isoquinolyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline

The title compound was prepared by the method of Example 23, from4-(3-aminophenyl)isoquinoline (0.41 g, 1.9 mmol),1,1′-carbonyldiimidazole (0.33 g, 2 mmol) and5-methoxy-6-trifluoromethylindoline (D11) (0.41 g, 1.9 mmol). Crudeproduct was chromatographed on silica gel eluted with 5%methanol/dichloromethane and eluted material was recrystallised fromdichloromethane to give the title compound (0.22 g, 25%), m.p. 211-5° C.

NMR (d₆(DMSO) δ: 3.28 (2H, t, J=8), 3.85 (3H, s), 4.21 (2H, t, J=8),7.20 (1H, d, J=7), 7.22 (1H, s), 7.50 (1H, t, J=8), 7.76 (2H, m), 7.78(1H, s), 7.82 (1H, t, J=7), 7.93 (1h, d, J=8), 8.1 (1H, s), 8.25 (1H, d,J=8), 8.47 (1H, s), 8.47 (1H, s), 8.73 (1H, s), 9.38 (1H, s).

Found: C, 67.01; H, 4.51; N, 9.03% C₂₆H₂₀N₃O₂F₃ required C, 67.38; H,4.35; N, 9.07%.

MS (API) 464 (MH⁺).

The mesylate salt can be prepared by treatment with methanesulphonicacid in acetone.

EXAMPLE 351-[5-(4-Methyl-3-pyridyl)-pyrid-3-ylcarbamoyl]-5-methoxy-6-trifluoromethylindoline(E35)

1-[5-Bromo-(3-pyridylcarbamoyl]-5-methoxy-6-trifluoromethylindoline(D26) (0.3 g 0.7 mmoles) and 4-methyl-3-pyridylboronic acid (0.12 g, 0.9mmoles) was heated under reflux in dimethoxyethane (80 ml) and water (10ml) with sodium carbonate (0.15 g, 1.4 mmoles) and palladium tetrakistriphenylphosphine (0.1 g, 12 mole %) under an inert atmosphere for 18hours. After cooling the mixture was partitioned between ethyl acetate(250 ml) and water (200 ml). The organic layer was separated and washedwith saturated sodium chloride solution then dried (Na₄SO₄). Evaporationof the solvent followed by flash chromatography on silica gel elutingwith 3-7% MeOH/CH₂Cl₂ and recrystallisation from ethyl acetate/60-80petrol gave the title compound (E35) (0.2 g, 65%) m.p. 125-8° C.

¹H NMR (CDCl₃) δ: 2.32 (3H, s), 3.32 (2H, t, J=8 Hz), 3.85 (3H, s), 4.18(2H, t, J=8 Hz), 6.90 (2H, s), 7.21 (1H, d, J=4 Hz), 8.10 (1H, s), 8.18(1H, s), 8.27 (1H, s), 8.40 (1H, s), 8.45-8.53 (2H, m).

M.S. found m/z 429 (MH⁺) C₂₂H₁₉N₄O₂F₃ requires 429.

EXAMPLE 361-[6-(3-Pyridyl)-pyrid-3-ylcarbamoyl]-5-methoxy-6-trifluoromethylindoline

Reaction of Phenyl N-[6-(pyrid-3-yl)pyrid-3-yl]carbamate (D27) (0.66 g,2.3 mmoles) with 5-methoxy-6-trifluoromethylindoline (D11) (0.5 g, 2.3mmoles) as in the method of example 28 gave the title compound (E36)(0.73 g, 78%), m.p.>270° C.

¹H NMR (DMSO-d⁶) δ: 3.32 (2H, t, J=8 Hz), 3.88 (3H, s), 4.23 (2H, t, J=8Hz), 7.20 (1H, s), 7.45-7.55 (1H, m), 7.98-8.18 (3H, m), 8.35-8.43 (1H,m), 8.55-8.60 (1H, m), 8.85 (1H, d, J=4 Hz), 8.91 (1H, s), 9.23 (1H, s).

MS (API) found m/z 415 (MH⁺) C₂₁H₁₇N₄O₂F₃ requires 415.

EXAMPLE 371-[5-(2-Furyl)-pyrid-3-ylcarbamoyl-5-methoxy-6-trifluoromethylindoline(E37)

This was prepared from1-(5-bromopyrid-3-ylcarbamoyl)-5-methoxy-6-trifluoromethylindoline and2-furylboronic acid by the same method as for Example 10, affording thetitle compound as a pale brown crystalline solid in 80% yield, m.p.92-94° C.

¹H NMR (D⁶-DMSO) 3.30 (2H, t), 3.85 (3H, s), 4.20 (2H, t), 6.65 (1H, m),7.10 (1H, d), 7.25 (1H, s), 7.85 (1H, s), 8.15 (1H, s), 8.30 (1H, t),8.60 (1H, d), 8.65 (1H, d), 8.90 (1H, bs).

EXAMPLE 381-[2-(4-Pyridyl)-thiazol-4-ylcarbamoyl-5-methoxy-6-trifluoromethylindoline

This was prepared from 2-(4-pyridyl)-thiazole-4-carboxylic acid by thesame methodology as for Description 15 and Example 19, affording thetitle compound as a yellow crystalline solid in 8% overall yield,m.p.>220° C.

¹H NMR (D⁶-DMSO) 3.30 (2H, t), 3.85 (3H, s), 4.20 (2H, t), 7.20 (1H, s),7.75 (1H, s,), 7.90 (2H, d), 8.15 (1H, s), 8.70 (2H, d), 9.90 (1H, bs).

EXAMPLE 391-[2-(Pyrazinyl)-thiazol-4-ylcarbamoyl]-5-methoxy-6-trifluoromethyl-indoline

This was prepared from 2-pyrazinyl-thiazole-4-carboxylic acid by thesame methodology as for Description 15 and Example 19, affording thetitle compound as a yellow crystalline solid in 45% overall yield,m.p.>240° C.

¹H NMR (D⁶-DMSO) 3.30 (2H, t), 3.85 (3H, s), 4.20 (2H, t), 7.20 (1H, s),7.75 (1H, s), 8.02 (1H, s), 8.75 (9.30 (1H, s), 9.90 (1H, s).

EXAMPLE 401-[3-(5-Pyrimidyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl-indoline

This was prepared from 3-(5-pyrimidyl)-aniline (D29) and5-methoxy-6-trifluoromethyl-indoline (D11), according to the method ofExample 1, affording the title compound in 69% yield as a whitecrystalline solid, m.p. 226-8° C.

¹H NMR (D⁶-DMSO) 3.30 (2H, t), 3.85 (3H, s), 4.20 (2H, t), 7.20 (1H, s),7.45 (2H, m), 7.70 (1H, m), 7.95 (1H, s), 8.15 (1H, s), 8.70 (1H, s),9.10 (2H, s), 9.02 (1H, s).

EXAMPLE 411-[3-4-Methyl-3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline

Reaction of phenyl-N-[3-(4-methylpyrid-3-yl]carbamate (D28) 0.4 g, 1.3mmoles) with 5-methoxy-6-trifluoromethylindoline (D11) (0.28 g, 1.3mmoles) as in the method of Example 28 gave the title compound (E41)(0.19 g, 34%) m.p. 178-180° C.

¹H NMR (DMSO-d⁶) δ: 2.29 (3H, s), 3.29 (2H, t, J=8 Hz), 3.84 (3H, s),4.19 (2H, t, J=8 Hz), 7.01 (1H, d, J=6 Hz), 7.20 (1H, s), 7.31-7.43 (2H,m), 7.55-7.62 (2H, m), 8.10 (1H, s), 8.32 (1H, s), 8.40 (1H, d, J=6 Hz),8.62 (1H, s).

M.S. (API) found m/z 428 (MH⁺) C₂₃H₂₀N₃O₂F₃ requires 428.

EXAMPLE 421-[5-Ethyl-3-(pyrid-3-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline

The title compound (0.15 g, 40%) was prepared as a tan powder using themethodology of Example 28 from phenyl N-(3-ethyl-5-(pyrid-3-yl)phenylcarbamate (D30) (0.26 g, 0.81 mmol) and5-methoxy-6-trifluoromethylindoline (D11) (0.177 g, 0.81 mmol) in DMF(10 ml). Melting point: 204° C.-207° C.

¹H NMR 250 MHz, CDCl, δ: 8.81 (s, 1H, Ar), 8.58 (d, 1H, Ar), 8.22 (s,1H, Ar), 7.88 (m, 1H, Ar), 7.48 (s, 1H, Ar), 7.32 (m, 2H, Ar), 7.12 (s,1H, Ar), 6.85 (s, 1H, Ar), 6.52 (s, 1H, NH), 4.12 (t, 2H, indoline),3.88 (s, 3H, Me), 3.28 (t, 2H, indoline), 2.60 (q, 2H, CH₂), 1.3 (t, 3H,Me).

Mass spec. m/z=442 [M⁺1]⁺.

Example 43 5-Methoxy-1-[5-phenyl-3-yl)phenylcarbamoyl]-6-trifluoromethylindoline (E43)

The title compound (0.74 g, 47%) was prepared as an off white solidusing the methodology of example 28, with phenylN-(5-phenyl-3-(pyrid-3-yl)phenyl)carbamate (D31) (0.27 g, 0.76 mmol) and5-methoxy-6-trifluoromethyl indoline (D11) [0.182 mg, 0.83 mmol) in DMF(10 ml). Melting point: 150°-151° C.

¹H NMR 250 MHz CDCl₃ δ: 8.87 (s, 1 H, Ar), 8.60 (d, 1 H, Ar), 8.24 (s, 1H, Ar), 7.90 (m, 1 H, Ar), 7.70-7.55 (m, 4 H, Ar), 7.50-7.30 (m, 5 H,Ar), 6.85 (br, 1 H, Ar), 6.65 (br, 1 H, NH), 4.12 (t, 2 H, indoline),3.85 (3 H, s, Me), 3.28 (t, 2 H, indoline)

Example 44 6-Chloro-5-methyl-1-[4-methyl-3-(4-methyl-3-pyridyl)phenylcarbamoyl]indoline

Reaction of phenyl N-[4-methyl-3-(4-methylpyrid-3-ylphenyl)carbamate(D69) (0.5 g, 1.6 mmoles) with 6-chloro-5-methylindoline (see WO95/01976) (0.26 g, 1.6 mmoles) as in the method of Example 28 gave thetitle compound (E44) (0.23 g, 38%) m.p. 178-180° C.

¹H NMR (CDCl₃) δ: 2.01 (3 H, s), 2.12 (3 H, s), 2.29 (3 H, s), 3.15 (2H, t, J=8 Hz), 4.07 (2 H, t, J=8 Hz), 6.60 (1 H, s), 6.95 (1 H, s),7.15-7.28 (3 H, m), 7.38-7.43 (1 H, m), 7.95 (1 H, s), 8.30 (1 H, s),8.42 (1 H,s)

MS (API) found m/z 392 (MH⁺, ³⁵Cl), 394 (MH⁺, ³⁷Cl)

C₂₃H₂₂N₃OCl requires 392, 394

Example 451-[3-(pyrid-3-ylaminocarbonyl)-phenylcarbamoyl]-5-methoxy-6-trifluoromethyl-indoline

A mixture of 3-(3-aminobenzoylamino)pyridine (D33) (0.416 g, 2 mmol) andcarbonyl diimidazole (0.34 g, 2 mmol) indichloromethane/N,N-dimethylformamide (25 ml/0.25 ml) was heated toreflux for 0.25 h, then evaporated to dryness. The residue was dissolvedin N,N-dimethylformamide (15 ml) and 5-methoxy-6-trifluromethyl indoline(0.416 g, 2 mmol) was added. The mixture was heated to 100° C. for 1 hthen treated with water (30 ml). Filtration and drying afforded a whitesolid (0.5 g). Chromatography on silica eluting with a gradient of 0-20%methanol in ethyl acetate afforded the title compound as a white solid(0.17 g, 19%), m.p.>220° C.

¹H NMR (D6-DMSO) 3.25 (2 H, t, J 8 Hz), 3.85 (3 H, s), 4.20 (2 H, t, J 8Hz), 7.25 (1 H, s), 7.40-7.55 (2 H, m), 7.65 (2 H, d, J 8 Hz), 7.90 (1H, d, J 8 Hz), 8.10-8.30 (3 H, m), 8.40 (1 H, d, J 2 Hz), 8.10-8.30 (3H, m), 8.40 (1 H, d, J 2 Hz), 8.85 (1 H, s), 8.90 (1 H, d, J 2 Hz),10.50 (1 H,s).

m/e 457 [MH]⊕ C₂₃H₁₉N₄F₃O₃ requires 457

Example 461-[3-(Pyrid-3-ylaminocarbonyl)-phenylcarbamoyl]-5-methylthio-6-trifluoromethyl-indoline

To a suspension of 5-methylthio-6-trifluoromethyl-1-(3-carboxy phenylcarbamoyl)indoline (D36) (0.5 g, 1.25 mmol) in dichloromethane was addedoxalyl chloride (0.324 g, 2.5 mmol) and dimethylformamide (3 drops).After effervescence has subsided the reaction mixture was evaporatedunder reduced pressure before being dissolved in tetrahydrofuran (10 ml)and added dropwise to a solution of 3-aminopyridine (0.133 mg, 1.4 mmol)and triethylamine (0.141 g, 1.4 mmol) in tetrahydrofuran (10 ml) at 0°C.

After 1 hour water was added forming a white precipitate which wasfiltered and dried to yield the product as a white solid (0.435 g, 73%),mp 195-7° C.

¹H NMR (DMSO) δ: 10.5 (1 H, s); 9.0 (2 H, d, J 5 Hz); 8.4 (1 H, d, J 5Hz); 8. (1 H, s); 8.25 (1 H, s); 8.2 (1 H, s); 7.9 (1 H, d, J 7 Hz); 7.7(1 H, d, J 7 Hz); 7.5 (3 H, m); 4.3 (2 H, t, J 8 Hz); 3.3 (2 H, t, J 8Hz); 2.5 (3 H, s)

Example 471-[3-(Pyrid-4-ylaminocarbonyl)-phenylcarbamoyl]-5-methylthio-6-trifluoromethylindoline

This was made in the same manner as Example 46 using a solution of4-aminopyridine to give the product as a peach solid (0.45 g, 76%),mp>200° C.

¹H NMR (DMSO) δ: 10.7 (1 H, s); 8.95 (1 H, s); 8.5 (2 H, d, J 7 Hz); 8.2(1 H, s); 8.1 (1 H, s); 7.85 (1 H, d, J 7 Hz); 7.8 (2 H, d, J 7 Hz);7.65 (1 H, d J 7 Hz); 7.45 (2 H, m); 4.25 (2 H, t, J 7 Hz); 3.3 (2 H, t,J 7 Hz); 2.5 (3 H, s )

m/e=472 C₂₃H₁₉F₃N₄O₂S requires 472

Example 481-[4-(Pyrid-3-ylaminocarbonyl)-phenylcarbamoyl]-5-methylthio-6-trifluoromethylindoline

This was made in the same manner as Example 46 using5-methylthio-6-tribluoromethyl-1-(4-carboxy phenyl carbamoyl) indoline(D37) to give the product as a pale yellow solid (0.327 g, 55%), mp>200°C.

¹H NMR (DMSO) δ: 10.6 (1 H, s); 9.1 (1 H, s); 9.0 (1 H, s); 8.4 (2 H, d,J 7 Hz); 8.2 (1 H, s); 8.0 (2 H, d, J 7 Hz); 7.8 (2 H, d, J 7 Hz); 7.6(1 H, q, J 5 Hz); 7.4 (1 H, s); 4.25 (2 H t, J 7 Hz); 3.3 (2 H, t, J 7Hz); 2.5 (3 H, s).

m/e=472 C₂₃H₁₉F₃N₄O₂S requires 472

Example 491-[4-(Pyrid-4-ylaminocarbonyl)-phenylcarbamoyl]-5-methylthio-6-trifluoromethylindoline

This was made in the same manner as Example 48 using a solution of4-aminopyridine to give the product as an orange solid (0.352 g, 59%),mp 158-160° C.

¹H NMR (DMSO) δ: 10.5 (1 H, s); 8.95 (1 H, s); 8.5 (2H, d, J 5 Hz); 8.2(1 H, s); 7.9 (2 H, d, J 7 Hz); 7.85 (2 H, d, J 5 Hz); 7.8 (2 H, d, J 7Hz); 7.5 (1 H, s); 4.25 (2 H, t, J 7 Hz); 3.3 (2 H, t, J 7 Hz); 2.5 (3H, s).

m/e=472 C₂₃H₁₉F₃N₄O₂5 requires 472

Example 501-[3-(3-pyridylcarbonyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline

The title compound (0.17 g, 26%) was prepared using the method ofExample 45, and purified by flash column chromatography on silica gel,eluting with 2% methanol/dichloromethane, and recyrstallisation fromethylacetate/methanol/60-80° petroleum ether.

¹H NMR (200 MHz; D⁶DMSO) δ: 3.28 (2 H, t), 3.75 (3 H, s), 4.20 (2 H, t),7.22 (1 H, s), 7.38-7.49 (1 H, m), 7.52 (1 H, t), 7.63 (1 H, q),7.93-8.00 (1 H, m), 8.02 (1 H, d), 8.08-8.20 (2 H, m), 8.78-8.99 (2 H,m), 9.02 (1 H, d)

Example 511-[3-(Pyrid-3-yl-aminosulphonyl)-phenylcarbamoyl]5-methoxy-6-trifluoromethyl-indoline

A suspension of 3-pyrid-3-ylaminosulphonyl)-aminobenzene (D39) (0.5 g, 2mmol) in chloroform (40 ml) was treated with triethylamine (5 ml) andchlorotrimethylsilane (5 ml). The solution was evaporated to dryness,and the residue dissolved in dichloromethane (20 ml). Carbonyldiimidazole (0.32 g, 2 mmol) was added and after 1 h the reactionmixture was evaporated to dryness. Dimethylformamide (20 ml) and5-methoxy-6-trifluoromethyl indoline (0.43 g, 2 mmol was added, and themixture heated to 100° C. for 2 h. the cooled solution was diluted withwater (60 ml). Filtration and drying afforded a brown solid (0.6 g).Chromatography, eluting with 0-5% methanol in ethyl acetate afforded theproduct as a white solid (0.26 g, 26%), m.p.>215° C.

¹H NMR (DMSO) δ: 10.60 (1 H, s), 8.9 (1 H, s), 8.30 (1 H, d, J 2 Hz),8.25 ( 1 H, dd, J 5 Hz), 8.20 (1 H, t, J 2 Hz), 8.10 (1 H, s), 7.80 (1H, d, J 7 Hz), 7.35-7.55 (3 H, m), 7.30 (1 H, m), 7.20 (1 H, s), 4.20 (2H, t, J 8 Hz), 3.85 (3 H, s), 3.25 (2 H, t, J 8 Hz)

Example 525-Methylthio-6-trifluoromethyl-1-[6-(pyridin-3-yloxy)pyridin-3-ylcarbamoyl)]indoline

5-Amino-2-(pyridin-3-yloxy)pyridine (0.5 g, 2.7 mmol) in dichloromethane(25 ml) was treated with triethylamine (0.4 ml, 2.9 mmol) then phenylchloroformate (0.34 ml, 2.7 mmol) dropwise at −20° C. The reactionmixture was allowed to warm to room temperature over 1 hour then pouredinto dilute aqueous sodium bicarbonate (50 ml). The organic phase wasseparated and the aqueous phase extracted with dichloromethane (2×50ml). The combined organic phases were dried (Na₂SO₄) and evaporated togive the crude phenyl carbamate (0.84 g) as a crystallising oil. Thismaterial was taken-up in dry DMF (10 ml) and triethylamine (0.5 ml) andtreated with 5-methylthio-6-trifluoromethyl indoline hydrochloride (0.63g, 2.32 mmol) at 100° C. for 0.5 h. After cooling the DMF was removedunder reduced pressure and the residue was partioned between 5% aqueoussodium hydroxide (100 ml) and dichloromethane (3×100 ml). The combinedorganic extracts were dried (Na₂SO₄) and evaporated. Chromatographyusing 2% methanol in ethyl acetate as eluant followed byrecrystallisation from ethyl acetate/petroleum ether (60-80°) gave thetitle compound (0.88 g, 73%) as a white crystalline solid m.p. 193-4° C.

¹H NMR (250 MHz, DMSO) δ: 3.28 (2 H, t, J 8 Hz), 3.37 (3 H, s), 4.20 (2H, t, J 8 Hz), 7.13 (1 H, d, J 9 Hz), 7.42-7.51 (2 H, m), 7.61 (1 H, m),8.08 (1 H, dd, J 8 Hz, 2 Hz), 8.21 (1 H, s), 8.27 (1 H, d, J 2 Hz),8.40-8.48 (2 H, m), 8.86 (1 H, s).

MS (EI) m/e=447 (MH⁺)

Example 535-Methoxy-6-trifluoromethyl-1-[6-(pyridin-3-yloxy)pyridin-3-ylcarbamoyl]indoline

5-Amino-2-(pyridin-3-yloxy)pyridine (0.2 g, 1.1 mmol) was treated withphenyl chloroformate to give the phenyl carbamate which was treated with5-methoxy-6-trifluoromethylindoline (0.23 g, 1.1 mmol) according to themethod of Example 52 to give the title compound (0.34 g, 74%) as a whitesolid m.p. 202-4° C.

¹H NMR (250 MHz, DMSO) δ: 3.28 (2 H, t, J 8 Hz), 3.86 (3 H, s), 4.18 (2H, t, J 8 Hz), 7.12 (1 H, d, J 9 Hz), 7.22 (1 H, s), 7.47 (1 H, dd, J 7Hz, 5 Hz), 7.51 (1 H, m, J 7 Hz), 8.08 (1 H, dd, J 8 Hz), 8.10 (1 H, s),8.27 (1 H, d, J 2 Hz), 8.40-8.47 (2 H, m), 8.78 (1 H, s).

MS (EI) m/e=431 (MH⁺)

Example 545-Methoxy-6-trifluoromethyl-1-[4-(pyridin-4-ylmethyloxy)phenylcarbamoyl]indoline

4-(Pyridin-4-ylmethyloxy)anailine (0.5 g, 2.5 mmol) was converted to thephenyl carbamate and treated with 5-methoxy-6-trifluoromethylindoline(0.54 g, 2.5 mmol) as in the method of Example 52. Chromatography usingethyl acetate as eluant followed by recrystallisation from ethylacetate/petroleum ether (60-80°) afforded the title compound (0.23 g,24%) as an off-white crystalline solid m.p. 205-207° C.

¹H NMR (250 MHz, CDCl₃) δ: 3.26 (2 H, t, J 8 Hz), 3.82 (3 H, s), 4.07 (2H, t, J 8 Hz), 5.06 (2 H, s), 6.29 (1 H, s), 6.83 (1 H, s), 6.91 (2 H,d, J 10 Hz), 7.28-7.48 (4 H, m), 8.22 (1 H, s), 8.60 (2 H, d, J 7 Hz).

MS (EI) m/e=444 (MH⁺)

Example 555-Methoxy-6-trifluoromethyl-1-[6-(pyridin-4-ylmethyloxy)pyridin-3-ylcarbamoyl]indoline

5-Amino-2-(pyridin-4-ylmethyloxy)pyridine (0.5 g, 2.5 mmol) wasconverted to the phenyl carbamate and treated with5-methoxy-6-trifluoromethylindoline (0.54 g, 2.5 mmol) as in the methodof Example 52. Chromatography using ethyl acetate as eluant followed byrecrystallisation from ethyl acetate/petroleum ether (60-80°) affordedthe title compound (0.13 g, 13%) as an off-white solid m.p. 187-189° C.

¹H NMR (250 MHz, CDCl₃) δ: 3.31 (2 H, t, J 8 Hz), 3.88 (3 H, s), 4.12 (3H, t, J 8 Hz), 5.40 (2 H, s), 6.32 (1 H, s), 6.88 (1 H, m), 7.35 (2 H,d, J 6 Hz), 7.91 (1 H, dd, J 8 Hz, 2 Hz), 8.04 (1 H, d, J 2 Hz), 8.22 (1H, s), 8.59 (2 H, d, J 6 Hz)

MS (EI) m/e=445 (MH⁺)

Example 565-Methylthio-6-trifluoromethyl-1-[4-(pyrid-4-(pyrid-4-yl-methylaminocarbonyl)phenyl carbamoyl]indoline

This was prepared by the same methodology as for Example 69 affordingthe title compound in 11% yield as a white solid m.p. 230-2° C.

¹H NMR (D6-DMSO) 2.50 (3 H, s), 3.25 (2 H, t), 3.45 (3 H, s), 4.20 (2 H,t), 7.15 (2 H, d), 7.25 (2 H, d), 7.50 (3 H, m), 8.20 (1 H, s), 8.45 (2H, d), 8.80 (1 H, s)

Example 57Trans-5-Methylthio-6-trifluoromethyl-1-{4-[2-ethenyl-(4-pyridyl)]-phenylcarbamoyl}-indoline

This was prepared from trans-4-[2-ethenyl-(4-pyridyl)]-aniline (D43) and5-methylthio-6-trifluoromethyl indoline (D7) using the phenylchloroformate procedure as for Description 18 and Example 26 affordingthe title compound as a yellow solid in 18% yield, m.p. 157-9° C.

¹H NMR (D6-DMSO) 2.50 (3 H, s), 3.30 (2 H, t), 4.25 (2 H, t), 7.15 (1 H,d), 7.45 (1 H, s), 7.55 (2 H, d), 7.65 (5 H, m), 8.25 (1 H, s), 8.55 (2H, d), 8.80 (1 H, s)

Example 585-Methylthio-6-trifluoromethyl-1-{4-[2-ethyl(4-pyridyl)]phenylcarbamoyl}indoline

This was prepared by hydrogenation of D42 followed by coupling with5-methylthio-6-trifluoromethyl indoline (D7) using the phenylchloroformate method, affording the title compound in 20% yield as awhite solid, m.p. 158-161° C.

¹H NMR (DMSO) 2.50 (3 H, s), 2.85 (4 H, m), 3.25 (2 H, t), 4.20 (2 H,t), 7.15 (2 H, d), 7.25 (2 H, d), 7.45 (4 H, m), 8.20 (1 H, s), 8.45 (2H, d), 8.60 (1 H, s).

Example 591-(1-(4-Pyridyl)5-indolylcarbamoyl)-5-methoxy-6-trifluoromethylindoline

The title compound was prepared by the method of Example 73, fromaminoindole (D53). Yield 62%, m.p. 206-211° C.

¹H NMR (CDCl₃) δ: 3.29 (2 H, t, J=8), 3.85 (3 H, s), 4.20 (2 H, t, J=8),6.78 (1 H, d, J=3), 7.20 (1 H, s), 7.41 (1 H, dd, J=8,2), 7.72 (2 H, d,J=6), 7.78 (1 H, d, J=8), 7.83 (1 H, d, J=3), 7.92 (1 H, d, J=2), 8.16(1 H, s), 8.58 (1 H, s), 8.70 (2 H, d, J=6)

MS (API) m/z=453 (MH⁺)

example 60 5-Methoxy-6-trifluoromethyl-1-[4-(pyridin-4-ylthiomethyl)phenylcarbamoyl]indoline

4-Pyridin-4ylthiomethyl)aniline (0.37 g, 1.71 mmol) was converted to thephenyl carbamate and treated with 5-methoxy-6-trifuloromethylindoline(D11) (0.37 g, 1.71 mmol) as in the method of Example 26 to give thetitle compound (0.5 g, 64%) as a white crystalline solid m.p. 174-5° C.

¹H NMR (250 MHz; DMSO) δ: 3.26 (2 H, t, J 8 Hz), 3.84 (3 H, s), 4.16 (2H, t, J 8 Hz), 4.32 (2 H, s), 7.20 (1 H, s), 7.32 (2 H, d, J 7 Hz), 7.37(2 H, d J 8 Hz), 7.52 (2 H, d, J 8 Hz), 8.11 (1 H, s), 8.37 (2 H, d, J 7Hz), 8.58 (1 H, s).

MS(EI) m/e=460 (MH⁺)

Example 615-Methoxy-6-trifluoromethyl-1-[4-(pyridin-4-ylsulphonylmethyl)phenylcarbamoyl]indoline

4-Pyridin-4-ylsulphonylmethyl)aniline was convested to the titlecompound according the method of Example 60 to give a white crystallinesolid (46%) m.p. 240-242° C.

¹H NMR (250 MHz; DMSO) δ: 3.26 (2 H, t, J 8 Hz), 3.84 (3 H, s), 4.17 (2H, t, J 8 Hz), 4.77 (2 H, s), 7.08 (2 H, d, J 8 Hz), 7.20 (1 H, d, J 8Hz), 7.70 (2 H, d, J 7 Hz), 8.10 (1 H, s), 8.59 (1 H, s), 8.88 (2 H, d,J 7 Hz)

MS (EI) m/e =492 (MH⁺)

Example 625-Methoxy-6-trifluoromethyl-1-[4-(pyridin-4-ylmethylthio)phenylcarbamoyl]indoline

4-(Pyridin-4-ylmethylthio)aniline was converted to the title compoundaccording to the method of Example 60 to give a white crystalline solid(63%) m.p. 160-3° C.

¹H NMR (250 MHz; CDCl₃) δ: 3.27 (2 H, t, J 8 Hz), 3.85 (3 H, s), 3.95 (2H, s), 4.08 (2 H, t, J 8 Hz), 6.41 (1 H, s), 6.84 (1 H, s), 7.12 (2 H,d, J 7 Hz), 7.23 (2 H, d, J 8 Hz), 7.33 (2 H, J 8 Hz), 8.21 (1 H, s),8.48 (2 H, d, J 7 Hz).

MS (EI) m/e=460 (MH⁺)

Example 635-Methylthio-6-trifluoromethyl-1-[(6-phenoxy)-3-pyridylcarbamoyl]-indoline

This was prepared from 6-phenoxy-3-aminopyridine and5-methylthio-6-trifluoromethylindoline (D7) by similar methodology toExample 1, affording the title compound as a yellow solid in 39% yield,m.p. 86-88° C.

NMR (D6-DMSO) 2.50 (3 H, s), 3.30 (2 H, t), 4.20 (2 H, t), 7.00 (1 H,d), 7.10 (2 H, m), 7.20 (1 H, m), 7.45 (3 H,), 8.05 (1 H, d), 8.20 (1 H,s), 8.30 (1 H, d), 8.85 (1 H, s).

Example 645-Methoxy-6-trifluoromethyl-1-[2-(pyridin-3-yloxy)pyridin-4-ylcarbamoyl)]indoline

4-Amino-2-(pyridin-3-yloxy)pyridine (D45) was converted to the titlecompound by the method of Example 60 to give an off-white crystallinesolid (89%) m.p. 223-5° C.

¹H NMR (250 MHz; DMSO) δ: 3.28 (2 H, t, J 8 Hz), 3.86 (3 H, s), 4.21 (2H, t, J 8 Hz), 7.24 (1 H, s), 7.39 (1 H, s), 7.40-7.52 (2 H, m), 7.62 (1H, m, J 9 Hz), 7.97 (1 H, d, J 7 Hz), 8.13 (1 H, s), 8.40-8.48 (2 H, m),9.10 (1 H, s).

Ms (EI) m/e=431 (MH⁺)

Example 65 5-Methylthio-6-trifluoromethyl-1-[6-(2-methylpyridin-3-yloxy)pyridin-3-ylcarbarmoyl]indoline

5-Amino-2-(2-methylpyridin-3-yloxy)pyridine was converted to the titlecompound according to the method of Example 60 to give a pale yellowsolid (30%) m.p. 204-7° C.

¹H NMR (250 MHz; DMSO) δ: 3.28 (2 H, t, J 8 Hz), 3.34 (3 H, s), 4.19 (2H, t, J 8 Hz), 7.10 (1 H, d, 8 Hz), 7.31 (1 H, dd, J 8 Hz), 7.44-7.53 (2H, m), 8.06 (1 H, dd, J 8 Hz, 2 Hz), 8.21 (1 H, s), 8.32 (2 H, d J 5Hz), 8.82 (1 H, s).

MS (EI) m/e=461 (MH⁺)

Example 66 5-Methylthio-6-trifluoromethyl-1-[6-(6-methylpyridin-3-yloxy)pyridin-3-ylcarbamoyl]indoline

5-Amino-2-(6-methylpyridin-3-yloxy)pyridine was converted to the titlecompound according to the method of Example 60 to give an off-whitesolid (44%) m.p. 206-8° C.

¹H NMR (250 MHz; DMSO) δ: 3.28 (2 H, t, J 8 Hz), 3.37 (3 H, s), 4.19 (2H, t, J 8 Hz), 7.09 (1 H, d, J 7 Hz), 7.32 (1 H, d, J 7 Hz), 7.45-7.53(2 H, m), 8.06 (1 H, dd, J 7 Hz, 2 Hz), 8.20 (1 H, s), 8.24 (1 H, d, J 2Hz), 8.30 (1 H, d, J 2 Hz), 8.84 (1 H, s).

MS (EI) m/e=461 (MH⁺)

Example 675-Methoxy-6trifluoromethyl-1-[6-(pyridin-3-ylthio)pyridin-3-ylcarbamoyl]indoline

5-Amino-2-(pyridin-3-ylthio)pyridine was converted to the title compoundaccording to the method of Example 60 to give a white crystalline solid(51%) m.p. 208-210° C.

¹H NMR (250 MHz; DMSO) δ: 3.28 (2 H, t, J 8 Hz), 3.85 (3 H, s), 4.17 (2H, t, J 8 Hz), 7.20 (1 H, d, J 7 Hz), 7.22 (1 H, s), 7.49 (1 H, dd, J 7Hz, 5 Hz), 7.90-7.99 (2 H, m), 8.11 (1 H, s), 8.57-8.68 (3 H, m), 8.84(1 H, s).

MS(EI) m/e=447 (MH⁺)

Example 68 5-Methylthio-6trifluoromethyl-1-[4-(pyrid-3-ylmethyl)amidophenylcarbamoyl]indoline

this was prepared in 61% yield by the same method as for Example 69,m.p.>250° C.

¹H MNR (D6-DMSO) δ: 2.50 (3 H, s) 3.30 (2 H, t), 4.25 (2 H, t), 4.50 (2H, d), 7.40 (1 H, m), 7.50 (1 H, s), 7.70 (3 H, m), 7.85 (2 H, d), 8.25(1 H, s), 8.45 (1 H, m), 8.55 (1 H, m), 8.80 (1 H, s), 9.00 (1 H, t)

Example 695-Methylthio-6-trifluoromethyl-1-[3-(pyrid-4-ylmethyl)amidophenylcarbamoyl]indoline

A suspenson of 5-methylthio-6-trifluoromethyl-1-(3-carboxyphenylcarbamoyl) indoline (D55) (0.5 g, 1.26 mmol) in dichloromethane (10 ml)was treated with oxalyl chloride (0.2 ml, 0.3 g, 2.4 mmol) andN,N-dimethyl formamide (3 drops). After 1 h the reaction mixture wasevaporated to dryness. The residue was dissolved in tetrahydrofuran (20ml) and added to a solution of 4-aminomethyl pyridine (0.15 ml, 1.39mmol) and triethylamine (0.2 ml, 0.15 g, 1.5 mmol) in tetrahydrofuran(10 ml at 0° C. After 1 h 5 M aqueous sodium hydroxide solution (5 ml)was added, followed by water (20 ml). Filtration and drying afforded theproduct as a yellow solid (0.58 g, 94%) m.p. 122-3° C.

¹H NMR (D6-DMSO) δ: 2.50 (3 H, s), 3.30 (2 H, t), 4.20 (2 H, t), 4.50 (2H, d), 7.30 (2 H, d), 7.40 (1 H, t), 7.45 (1 H, s), 7.60 (1 H, d), 7.80(1 H, d), 8.05 (1 H, s), 8.25 (1 H, s), 8.50 (2 H, d), 8.85 (1 H, bs),9.15 (1 H, t)

Example 705-Methylthio-6-trifluoromethyl-1-[4-(pyrid-2-ylmethyl)amidophenylcarbamoyl]indoline

This was prepared by the same method as for Example 69, affording thetitle compound as a white solid in 84% yield, m.p. 203-5° C.

¹H NMR (D6-DMSO) δ: 2.50 (3 H, s), 3.30 (2 H, t), 4.20 (2 H, t), 4.55 (2H, d), 7.25-7.35 (2 H, m), 7.45 (1 H, s), 7.65-7.75 (3 H, m), 7.90 (2 H,d), 8.25 (1 H, s), 8.50 (1 H, d), 8.85 (1 H, s), 9.00 (1 H, t).

Example 711-(1-(3-Pyridylmethyl)-5-indolylcarbamoyl)-5-methoxy-6-trifluoromethylindoline

A solution of aminoinide (D48, 0.40 g, 1.8 mmol) and1,1′-carbonyldiimidazole (0.30 g, 1.8 mmol) in dichloromethane (40 mL)was stirred at room temperature for 1.75 h, then evaporated. To theresidue was added dimethylformamide (DMF, 10 mL) and a solution of5-methoxy-6-trifluoromethylindoline (D11, 0.39 g, 1.8 mmol) in DMF (5mL). The mixture was stirred at 110° C. overnight, then poured intowater and extracted with dichloromethane. The extract was washed withwater, dried and evaporated. The residue was triturated with ether togive a grey solid, which was recrystallised fromdichloromethane/methanol to give the title compound (0.15 g, 18%) m.p.243-6° C.

¹H NMR (CDCl₃)δ: 3.26 (2H, t, J=8), 3.83 (3H, s), 4.17 (2H, t, J=8),5.45 (2H, s), 6.45 (1H, d, J=3), 7.19 (1H, s), 7.22 (1H, d, J=8), 7.33(1H, dd, J=7,5), 7.42 (1H, d, J=8), 7.51 (1H, d, J=3), 7.5 (1H, d, J=8),7.72 (1H, s), 8.12 (1H, s), 8.41 (1H, s), 8.46 (1H, d, J=5), 8.51 (1H,s)

MS(API)m/z=467 (MH⁺)

Example 721-(1-(4-Pyridylmethyl)-5-indolylcarbamoyl)-5-methoxy-6-trifluoromethylindoline

A mixture of aminoindole (D49, 0.46 g, 2.1 mmol), phenyl chloroformante(0.26 mL, 2.1 mmol) and triethylamine (0.29 mL, 2.1 mmol) indichloromethane (5 mL) was stirred at room temperature for 1 h. Themixture was then diluted with dichloromethane, washed with water, driedand evaporated. The residue was dissolved in acetonitrile (10 mL).5-Methoxy-6-trifluoromethylindoline (D11, 0.45 g, 2.1 mmol) andtriethylamine (0.29 mL, 2.1 mmol) were added and the mixture was stirredfor 3 h at room temperature. The reaction was worked up as for Example71, and the solid obtained after trituration was recrystallised fromdichloromethane/petrol to give the title compound (0.26 g, 27%), m.p.215-8° C.

¹H NMR (CDCl₃)δ: 3.26 (2H, J=8), 3.83 (3H, s), 4.16 (2H, t,J=8), 5.48(2H,s), 6.49 (1H, d,J=3), 7.04 (2H, d, J=6), 7.20 (2H, m), 7.30 (1H, d,J=8), 7.49 (1H, d, J=3), 7.73 (1H, s), 8.12 (1H, s), 8.42 (1H, s), 8.47(2H, d, J=6).

MS(API) m/z=467 (MH⁺)

Example 731-(1-(3-pyridyl)-5-indolylcarbamoyl)-5-methoxy-6-trifluoromethylindoline

The title compound was prepared by the method of Example 72, fromaminoindoline (D52, 0.34 g, 1.63 mmol). Addition of the reaction mixtureto water gave a precipitate which was filtered off, dried andrecrystallised from dichloromethane/petrol to give the title compound(0.61 g, 84%), m.p. 202-4° C.

¹H NMR (CDCl₃) δ: 3.28 (2H, t, J=8), 3.84 (3H, s), 4.19 (2H, t, J=8),6.73 (1H, d, J=3), 7.21 (1H, s), 7.38 (1H, dd, J=8,2), 7.55 (1H, d,J=8), 7.62 (1H, dd, J=7,5), 7.73 (1H, d, J=3), 7.89 (1H, d, J=2), 8.09(1H, d, J=7), 8.17 (1H, s), 8.55 (1H, s), 8.60 (1H, d, J=5), 8.89 (1H,d, J=2).

MS(API) m/z=453(MH⁺)

Example 745-Methylthio-6-trifluoromethyl-1-{3-[2-(3-pyridyl)thiazol-4-yl]phenylcarbamoyl}indoline

A solution of 4-(3-aminophenyl)-2-(3-pyridyl)-thiazole (0.76 g, 3 mmol)in chloroform (30 ml) was added to a solution of carbonyl diimidazole(0.49 g, 3 mmol) in dichloromethane (10 ml). After 1 h the mixture wasevaporated. 5-Methylthio-6-trifluoromethyl indoline (0.7 g, 3 mmol) andN,N-dimethylformamide (20 ml) were added. The mixture was heated at 100°C. for 1 h, then diluted with water (50 ml). Filtration and evaporatedafforded a yellow solid (1.1 g). Recrystallisation from ethylacetate-petrol afforded the title compound as a white solid (0.53 g,35%), m.p. 154-5° .

¹H NMR (DMSO) 2.50 (3H, s), 3.30 (2H, t), 4.25 (2H, t), 7.45 (1H, t),7.50 (1H, s), 7.55 (2H, m), 7.70 (1H, m), 8.25 (2H, m), 8.40 (1H, dt),8.70 (1H, d), 8.80 (1H, s), 9.25 (1H, d).

Example 755-Methylthio-6-trifluoromethyl-1-{4-[2-(4-pyridyl)-thiazol-4-yl]phenylcarbamoyl}indoline

This was prepared in the same manner as5-methylthio-6-trifluoromethyl-1-{3-[2-(3-pyridyl)-thiazol-4-yl]phenylcarbamoyl} indoline to give the product as a yellow solid (0.2 g, 31%),m.p. 253-4° C.

¹H NMR (DMSO) δ: 8.8 (3H, m), 8.2 (2H, s), 8.0 (4H, m), 7.7 (2H, d), 7.4(1H, s), 4.2 (2H, t), 3.3 (2H, t), 2.5 (3H, s)

Example 765-Methylthio-6-trifluoromethyl-1-{4-[2-(3-pyridyl)-thiazol-4-yl]phenylcarbamoyl}indoline

This was prepared in the same manner as5-methylthio-6-trifluoromethyl-1-{3-[2-(3-pyridyl)-thiazol-4-yl]phenylcarbamoyl} indoline to give the product as a yellow solid (0.25 g, 39%),m.p.>250° C.

¹H NMR (DMSO) δ: 9.2 (1H, s), 8.8 (1H, s), 8.7 (1H, d), 8.4 (1H, d), 8.2(1H, s), 8.1 (1H, s), 7.95 (2H, d), 7.7 (2H, d), 7.6 (1H, q), 7.4 (1H,s), 4.2 (2H, t), 3.3 (2H, t), 2.5 (3H, s)

Example 771-[4-Fluoro-3-(3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline

A solution of 4-fluoro-3-(pyrid-3-yl)phenylcarbonyl azide (D59) (270 mg,1.1 mmol) in toluene (10 ml) was refluxed under argon for 45 minutes andcooled. To a stirred solution of the indoline (D11) (266 mg, 1.1 eq) indichloromethane was added the isocyanate solution. The total solutionwas stirred at room temperature overnight, evaporated to dryness andchromatographed (EtOAc→5% MeOH/EtOAc, SiO₂). Concentration of fractionsafforded the title compound as a white powder (315 mg, 66%). Meltingpoint=210-212° C.

¹H NMR (250 MHz, δ: 8.73 (d, 2H), 860 (dd, 1H), 8.10 (s, 1H), 7.97 (dd,1H), 7.75 (m, 1H), 7.65 (m, 1H), 7.54 (m, 1H), 7.30 (t, 1H), 7.21 (s,1H), 4.15 (t, 2H), 3.83 (s, 3H), 3.27 (t, 2H).

Mass spec: m/z=432 MH⁺

Example 781-[3-Fluoro-5-(pyrimidin-5-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline

3-Fluoro-5-(pyrimidin-5-yl)phenylcarbonyl azide (D60) (0.22 g, 0.00091mole) was dissolved in dry toluene (15 ml) and heated under reflux underargon for {fraction (1/2 )} hour. After cooling to ambient temperature,5-methoxy-6-trifluoromethyl indoline (D11) (0.20 g, 0.00091 mole) indichloromethane (8 ml) was added and the mixture stirred for 18 h. Thedichloromethane was removed in vacuo and the resulting precipitatefiltered and dried in vacuo. This was recrystallised from ethylacetate/60-80° petroleum ether to afford the title compound (0.17 g,43%).

¹H NMR (200 MHz, D⁶DMSO) δ(ppm): 3.30 (2H, t, J=8), 3.87 (3H, s), 4.20(2H, t, J=8), 7.22 (1H, s), 7.38 (1H, dt, J=3, 9), 7.68 (1H, dt, J=3,11), 7.79 (1H, s), 8.14 (1H, s), 8.90 (1H, s), 9.12 (2H, s), 9.24 (1H,s).

Example 791-[4-Chloro-3-(4-methyl-3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline

4-Chloro-3-(4-methyl-3-pyridyl)aniline (D62) was converted to the phenylcarbamate in the usual manner and then treated with5-methoxy-6-trifluoromethylindoline (D11). Purification of the residueobtained by flash chromatography on silica gel gave the title compound(E79) (0.115 g, 49%) m.p. 140-141° C.

¹H NMR (CDCl₃) δ: 2.19 (3H, s), 3.28 (2H, t, J=8 Hz), 3.82 (3H, s), 4.15(2H, t, J=8 Hz), 6.81 (1H, s), 7.09 (1H, s), 7.20 (1H, d, J=6 Hz), 7.25(1H, s), 7.40 (1H, d, J=8 Hz), 7.52-7.69 (1H, m), 8.20 (1H, s), 8.30(1H, s), 8.45 (1H, d, J=6 Hz).

Example 801-[2,3-Dihydro-7-(pyrid-3-yl)benzofuran-5-ylcarbamoyl]-5-methoxy-6-trifluoromethylindoline

Phenyl N-[2,3-dihydro-7-(pyrid-3-yl)benzofuran-5-yl]carbamate (D65)(0.20 g, 0.00060 mole) in dry DMF (10 ml) was treated under argon with5-methoxy-6-trifluoromethyl indoline (D11) (0.13 g, 0.00060 mole) andheated under reflux for 18 hours. The reaction was allowed to cool toambient temperature and the solvent was removed in vacuo. The residuewas dissolved in dichloromethane, washed with deionised water and 10%sodium hydroxide solution, dried (Na₂SO₄) and evaporated in vacuo. Theresulting brown oil was purified by flash column chromatography onsilica gel, eluting with 2% methanol/dichloromethane, followed byrecrystallisation from ethyl acetate 60-80° petroleum ether to affordthe title compound (0.07 g, 26%) as a beige solid.

¹H NMR (200 MHz, D⁶DMSO) δ(ppm): 3.12-3.49 (4H, m), 3.85 (3H, s), 4.15(2H, t, J=8), 4.61 (2H, t, J=10), 7.21 (1H, s), 7.40-7.58 (3H, m), 8.07(1H, dt, J=1, 7), 8.13 (1H, s), 8.43-8.60 (2H, m), 8.88 (1H, d, J=1).

Example 815-Methoxy-6-trifluoromethyl-1-[6-(2-methylpyridin-3-yloxy)pyridin-3-ylcarbamoyl]indoline

5-Amino-2-(2-methylpyridin-3-yloxy)pyridine was converted to the titlecompound according to the method of Example 60 to give a whitecrystalline solid (71% ) m.p. 227-230° C.

¹H NMR (250 MHz, DMSO) δ: 3.28 (2H, t, J8 Hz), 3.85 (3H, s), 4.15 (2H,t, J8 Hz), 7.09 (1H, d, J8 Hz), 7.21 (1H, s), 7.30 (1H, dd, J8 Hz, 5Hz), 7.49 ( 1H, d, J8 Hz), 8.04 (1H, dd, J8 Hz, 2 Hz), 8.10 (1H, d, J2Hz), 8.32 (1H, d, J5 Hz), 8.72 (1H, s).

MS(EI) m/e=445 (MH⁺)

Example 825-Methoxy-6-trifluoromethyl-1-[6-(4-methylpyridine-3-yloxy)pyridin-3-ylcarbamoyl]indoline

5-Amino-2-(4-methylpyridin-3-yloxy)pyridine was converted to the titlecompound according to the method of Example 60 to give a whitecrystalline solid (51%) m.p. 188-191° C.

¹H NMR (250 MHz, DMSO) δ: 3.30 (2H, t, J8 Hz), 3.83 (3 H, s), 4.15 (2H,t, J8 Hz), 7.10 (1H, d, J8 Hz), 7.20 (1H, s), 7.38 (1H, d, J5 Hz), 8.04(1H, dd, J8 Hz, 2Hz), 8.10 (1H, s), 8.17 (1H, d, J2 Hz), 8.29 (1H, s),8.30 (1H, d, J5 Hz), 8.72 (1H, s).

MS (EI) m/e=445 (MH⁺)

The following examples were prepared using similar techniques:

Example No. R₁ R₂ R₃ M. Pt. ° C.  83 3-(3-Pyridyl)phenyl OMe CF₃ 192-193 84 2-Methoxy-3-(3-pyridyl)phenyl OMe CF₃ 196-197  852-Chloro-3-(3-pyridyl)phenyl OMe CF₃ 214-216  86 3-(3-Quinolyl)phenylOMe CF₃ 240 (dec.)  87 5-(4-Fluorophenyl)-3-pyridyl OMe CF₃ >200  885-(3,5-Difluorophenyl)-3-pyridyl OMe CF₃ 226-229  895-(4-Chlorophenyl)-3-pyridyl OMe CF₃ 198-199  905-(2-Methylphenyl)-3-pyridyl OMe CF₃ 103-105  915-(2-Formylphenyl)-3-pyridyl OMe CF₃ 114-116  925-(2-Hydroxymethylphenyl)-3-pyridyl OMe CF₃ 190-192  935-(3-Chloro-4-fluorophenyl)-3-pyridyl OMe CF₃ 113-115  946-Phenyl-3-pyridyl OMe CF₃ 204-207  95 5-(3-pyridyl)-2-pyridyl OMeCF₃ >225  96 6-(1-Pyrazolyl)-3-pyridyl OMe CF₃ >225  973-(4-N,N-Dimethylaminophenyl)phenyl OMe CF₃ 213-215  983-(4-N,N-Dimethylaminomethylphenyl)phenyl OMe CF₃ 209-211  993-(3-N,N-Dimethylaminomethylphenyl)phenyl OMe CF₃ 185-187 1003-(5-N,N-Dimethylaminomethyl-1,2,4-oxadiazol-3-yl)phenyl OMe CF₃ 154-155101 3-(1-Dimethylaminoethyl-2-pyrrolyl)phenyl OMe CF₃ 158-159 1023-(2-Pyrrolyl)phenyl OMe CF₃ >240 103 3-(3-Pyridyl)phenyl Me Cl 208-210104 5-Ethenyl-3-(3-pyridyl)phenyl OMe CF₃ 138-140 1053-(3-Pyridyl)-5-(trifluoromethyl)phenyl OMe CF₃ 220-222 1065-Chloro-3-(3-pyridyl)phenyl OMe CF₃ 183-185 1075-Acetyl-3-(3-pyridyl)phenyl OMe CF₃ 174-176 1084-Methoxy-3-(3-pyridyl)-5-(trifluoromethyl)phenyl OMe CF₃ 180-181 1094-Methyl-3-(4-methyl-3-pyridyl)phenyl OMe CF₃ 153-155 1103-(2-Methyl-3-pyridyl)phenyl OMe CF₃ 179-180 1113-(2,4-Dimethyl-3-pyridyl)phenyl OMe CF₃ 202-204 1123-(6-Methyl-3-pyridyl)phenyl OMe CF₃ 228-230 1133-(2-Methyl-4-pyrimidinyl)phenyl OMe CF₃ >220 1143,5-(Di-3-pyridyl)phenyl OMe CF₃ 155-156 1153-(3-Pyridyl)-5-(4-pyridyl)phenyl OMe CF₃ 153-154 1165-Fluoro-3-(6-methyl-3-pyridyl)phenyl OMe CF₃ 213-215 1173-(4,6-Dimethyl-3-pyridyl)phenyl OMe CF₃ 161-162 1185-Fluoro-3-(3-pyridazinyl)phenyl OMe CF₃ 230-231 1193-(5-Pyrimidinyl)phenyl OMe CF₃ 245-250 120 3-(2-Pyrazinyl)phenyl OMeCF₃ 208-209 121 3-(6-Methyl-3-pyridazinyl)phenyl OMe CF₃ 229-231 1223-(3-Pyridyl)-5-(trifluoromethoxy)phenyl OMe CF₃ 168-170 1233-(3-Pyridyl)-4-(trifluoromethoxy)phenyl OMe CF₃  99-100 1245-Fluoro-4-methyl-3-(3-pyridyl)phenyl OMe CF₃ 244-247 1255-Fluoro-3-(2-methyl-3-pyridyl)phenyl OMe CF₃ 204-205 1265-Fluoro-3-(2-pyrazinyl)phenyl OMe CF₃ 230-231 1275-Fluoro-3-(4,6-dimethylpyrid-3-yl)phenyl OMe CF₃ 215-218 1285-Fluoro-4-methyl-3-(pyrimidin-3-yl)phenyl OMe CF₃ 188-189 1295-Fluoro-4-methyl-3-(pyrid-3-yl)phenyl Me Cl 233-235 1305-(5-Pyrimidinyl)-3-pyridyl OMe CF₃  120-121, 215-216 1315-Fluoro-3-(2-pyrazinyl)phenyl Me Cl 226-227 1325-Fluoro-3-(5-pyrimidinyl)phenyl Me Cl 222-226 133 3-(3-Pyridyl)phenylC(Me₂)CH₂CH₂ 91-92 134 5-Fluoro-3-(2-methyl-3-pyridyl)phenyl Me Cl205-206 135 4-Fluoro-3-(3-pyridyl)phenyl Cl Cl 200-202 1364-Fluoro-3-(3-pyridyl)phenyl Me Cl 185-186 1373-(Pyrid-3-ylmethyloxy)phenyl OMe CF₃ 202-204 1384-(Pyrid-3-ylmethyloxy)phenyl OMe CF₃ 215-217 1393-(Pyrid-3-yloxymethyl)phenyl OMe CF₃ 188-190 1405-Methyl-6-(pyrid-3-yl)pyrid-3-yl OMe CF₃ 230-232 1415-Chloro-6-(pyrid-3-yl)pyrid-3-yl SMe CF₃ 245-250 1426-(5-Chloropyrid-3-yl)pyrid-3-yl SMe CF₃ 193-195 1434-(Pyrid-3-yloxy)phenyl OMe CF₃ 193-194 144 6-(Pyrid-3-ylthio)pyrid-3-ylSMe CF₃ 204-206 145 6-(Pyrid-4-ylthio)pyrid-3-yl SMe CF₃ 214-216 1466-(Pyrid-4-ylthio)pyrid-3-yl OMe CF₃ 204-206 1474-(Pyrid-4-ylmethyl)phenyl SMe CF₃ 206-209 1483-(Pyrid-3-ylmethylaminocarbonyl)phenyl SMe CF₃ 210-215 1493-[3-(Pyrid-2-yl)propionyl]phenyl SMe CF₃ 145-146 1503-[3-(Pyrid-2-yl)-1-hydroxypropyl]phenyl SMe CF₃ 78-80 1514-(Pyrid-4-ylmethylaminocarhonyl)phenyl SMe CF₃ 138-140 1523-[1-(Pyrid-2-yl)propionyl]phenyl SMe CF₃ 110-112 1533-[2-(Pyrid-2-yl)ethylcarbamoyl]phenyl SMe CF₃ 92-94 1543-[(Pyrid-2-yl)methylcarbamoyl]phenyl SMe CF₃ 116-118 1556-(Phenoxy)pyrid-3-yl OMe CF₃ 202-203 1566-(2,4-Dimethylpyrid-3-yloxy)pyrid-3-yl OMe CF₃ 218-221 1576-(2-Methylphenoxy)pyrid-3-yl OMe CF₃ 226-228 1586-(3-Methoxyphenoxy)pyrid-3-yl OMe CF₃ 188-189 1596-(4-Fluoro-2-methylphenoxy)pyrid-3-yl OMe CF₃ 208-209 1606-(2,4-Dimethylphenoxy)pyrid-3-yl OMe CF₃ 236-238 1616-(2-Chloropyrid-3-yloxy)pyrid-3-yl OMe CF₃ 238-240 1626-(2-Ethylphenoxy)pyrid-3-yl OMe CF₃ 215-220 1636-(4-Carbamoylphenoxy)pyrid-3-yl OMe CF₃ 245-248 1646-(2-Trifluoromethylphenoxy)pyrid-3-yl OMe CF₃ 237-238 1656-(3-Trifluoromethylphenoxy)pyrid-3-yl OMe CF₃ 193-194 1666-(2,6-Dimethylpyrid-3-yloxy)pyrid-3-yl OMe CF₃ 230-233 1676-(2-Methylpyrid-3-yloxy)pyrid-3-yl Me Cl 181-183 1686-(2-Methylpyrid-3-yloxy)pyrid-3-yl Cl Cl 225-228 1694-Fluoro-3-(5-pyrimidinyl)phenyl Cl Cl 132-135 1705-Fluoro-3-(5-pyrimidinyl)phenyl Cl Cl 260 1714-Fluoro-3-(5-pyrimidinyl)phenyl Me Cl 211-213 1725-Fluoro-3-(5-pyrimidinyl)phenyl Br CF₃ 214-218 1736-(2-Methyl-1-oxopyrid-3-yloxy)pyrid-3-yl OMe CF₃ 252-257 1744-Fluoro-3-(3-pyridyl)phenyl Br CF₃ 200-201 1756-(3-Cyanophenoxy)pyrid-3-yl OMe CF₃ 136-138 1766-(4-Cyanophenoxy)pyrid-3-yl OMe CF₃ 188-189 1776-(2-Methylpyrid-3-yloxy)pyrid-3-yl Br CF₃ 211-213

Pharmacological data

[³H]-mesulergine binding to rat or human 5-HT_(2C) clones expressed in293 cells in vitro

Compounds were tested following the procedure outlined in WO 94/04533.The compounds of examples 1 to 165 have pKi values of 5.8 to 9.7.

Reversal of MCPP-induced Hypolocomotion

Compounds were tested following the procedure outlined in WO 94/04533.The compound of examples 1, 3, 7, 8, 21, 24, 25, 26, 31, 40, 42, 52, 53,54, 55, 77, 78, 79, 80 and 81 have ID_(50's) between 0.5 and 5.5 mg/kgp.o.

What is claimed is:
 1. A compound of formula (I) or a salt thereof:

wherein: P¹ is pyridyl; P² is pyridyl; A is a bond or a chain of 1 to 5atoms optionally substituted by C₁₋₆alkyl; R¹ and R² groups are eachindependently hydrogen C₁₋₆alkyl optionally substituted by NR¹²R¹³,C₂₋₆alkenyl, C₂₋₆alkynyl, cyano, halogen, CF₃, NR¹²R¹³, CHO, OCF₃,COR¹⁴, CH₂OR¹⁴ or OR¹⁴ where R¹², R¹³ and R¹⁴ are independently hydrogenor C₁₋₆alkyl; n and m are independently 0, 1 or 2; R³ is hydrogen orC₁₋₆alkyl; R⁴ is a group of formula (i):

in which: R⁶ and R⁷ are independently hydrogen, C₁₋₆ alkyl optionallysubstituted by one or more fluorine atoms, C₁₋₆alkylthio, C₁₋₆alkoxy orhalogen or a pharmaceutically acceptable salt thereof.
 2. A compoundaccording to claim 1 in which A is a bond.
 3. A compound according toclaim 1 in which R² is hydrogen, halogen, methyl, CF₃ or OCF₃.
 4. Acompound according to claim 1 in which R³ is hydrogen.
 5. A compoundaccording to claim 1 in which R⁶ is trifluoromethyl or halogen and R⁷ isC₁₋₆ alkoxy, C₁₋₆alkylthio or C₁₋₆alkyl.
 6. A compound according toclaim 1 which is:1-[5-(3-Pyridyl)-pyrid-3-ylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,1-[5-(4-Pyridyl)-pyrid-3-ylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,1-[5-(4-Methyl-3-pyridyl)-pyrid-3-ylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,1-[6-(3-Pyridyl)-pyrid-3-ylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,5-Methylthio-6-trifluoromethyl-1-[6-(pyridin-3-yloxy)pyridin-3-ylcarbamoyl)]indoline,5-Methoxy-6-trifluoromethyl-1-[6-(pyridin-3-yloxy)pyridin-3-ylcarbamoyl)]indoline,5-Methoxy-6-trifluoromethyl-1-[6-(pyridin-4-ylmethyloxy)pyridin-3-ylcarbamoyl)]indoline,5-Methoxy-6-trifluoromethyl-1-[2-(pyridin-3-yloxy)pyridin-4-ylcarbamoyl)]indoline,5-Methylthio-6-trifluoromethyl-1-[6-(2-methylpyridin-3-yloxy)pyridin-3-ylcarbamoyl)]indoline,5-Methylthio-6-trifluoromethyl-1-[6-(6-methylpyridin-3-yloxy)pyridin-3-ylcarbamoyl)]indoline,5-Methoxy-6-trifluoromethyl-1-[6-(pyridin-3-ylthio)pyridin-3-ylcarbamoyl)]indoline,5-Methoxy-6-trifluoromethyl-1-[6-(2-methylpyridin-3-yloxy)pyridin-3-ylcarbamoyl)]indoline,5-Methoxy-6-trifluoromethyl-1-[6-(4-methylpyridin-3-yloxy)pyridin-3-ylcarbamoyl)]indoline,and pharmaceutically acceptable salts thereof.
 7. A pharmaceuticalcomposition which comprises an effective amount of a compound accordingto claim 1 and a pharmaceutically acceptable carrier or excipient.
 8. Aprocess for the preparation of a compound of formula (I) or apharmaceutically acceptable salt thereof, which process comprises: (a)the coupling of a compound of formula (II);

with a compound of formula (III); D-R^(4′)  (III) wherein A, P¹ and P²are as defined in formula (I), C and D contain the appropriatefunctional groups(s) necessary to form the moiety —NR^(3′)CO whencoupled, the variables R^(1′), R^(2′), R^(3′) and R^(4′) are R¹, R², R³and R⁴ respectively, as defined in formula (I), or groups convertiblethereto, and thereafter optionally and as necessary and in anyappropriate order, converting any R^(1′), R^(2′), R^(3′) and R^(4′),when other than R¹, R², R³ and R⁴ respectively to R¹, R², R³ and R⁴,interconverting R¹, R², R³ and R⁴ and forming a pharmaceuticallyacceptable salt thereof; or (b) the coupling of a compound of formula(IV);

with a compound of formula (V);

wherein P¹, P², R^(1′), R^(2′), R^(3′) and R^(4′) are as defined aboveand E and G contain the appropriate functional group(s) necessary toform the A moiety when coupled and thereafter optionally and asnecessary and in any appropriate order, converting any R^(1′), R^(2′),R^(3′) and R^(4′), when other than R¹, R², R³ and R⁴ respectively to R¹,R², R³ and R⁴, interconverting R¹, R², R³ and R⁴ and forming apharmaceutically acceptable salt.
 9. A method of antagonizing 5HT_(2C)receptors by administering to patient in need thereof, an effectiveamount of a compound of claim
 1. 10. A method of treating CNS disordersby administering to a patient in need thereof, an effective amount of acompound of claim
 1. 11. A method of treating anxiety or depression byadministering to a patient in need thereof, an effective amount of acompound of claim 1.